\r\n\tThis book intends to provide readers with a comprehensive overview of the basic mechanisms of siRNA, progress in the development of safer delivery vehicles, current developments in siRNA-based therapeutics and state-of-the-art technology and platforms with evidence-based clinical applications of siRNA.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:null,priceUsd:null,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"c29da6fa3e8417ec0dde73b0cb79a7d0",bookSignature:"Dr. Muhammad Nawaz",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8132.jpg",keywords:"RNAi, siRNA, biogenesis, RISC, gene expression regulation,\r\nefficiency of encapsulation, exogenous loading, siRNA delivery methods and systems, Analytical methodology, Delivery efficiency, cytosolic release, targeted gene silencing,Therapeutic applications of siRNA",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 15th 2019",dateEndSecondStepPublish:"March 8th 2019",dateEndThirdStepPublish:"May 7th 2019",dateEndFourthStepPublish:"July 26th 2019",dateEndFifthStepPublish:"September 24th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"199581",title:"Dr.",name:"Muhammad",middleName:null,surname:"Nawaz",slug:"muhammad-nawaz",fullName:"Muhammad Nawaz",profilePictureURL:"https://mts.intechopen.com/storage/users/199581/images/system/199581.jpg",biography:"Dr. Nawaz is an academic researcher at the University of Gothenburg, Sweden, having expertise in the area of Biochemistry & Molecular Biology. Dr. Nawaz did his PhD from University of Sao Paulo, Ribeirao Preto Medical School (Brazil), where he worked on transcriptomic and microRNAs (miRNAs) profiling in the malignant progression of brain tumors (gliomas) with an aim to identify potential therapeutic targets and non-invasive biomarkers. During his PhD, Dr. Nawaz was granted with fellowship from FAPESP (the highest ranked funding body in Brazil), and was also awarded with Science without borders mobility award from Brazilian higher education agency (CAPES) to join the University of Gothenburg for one year PhD exchange, where he worked on mechanisms of packaging therapeutic RNAs into exosomes, which are now used as RNA delivery vehicles. Later, he continued his Postdoc at the University of Gothenburg. He has also served community services, and is the founder of Biochemists Association QUA Islamabad (BAQI), and is junior member of international society for extracellular vesicles (ISEV). Dr. Nawaz has won several awards, both from Brazil, and Sweden, has participated in several international conferences, and has published research papers in reputed peer reviewed international journals. He also serves as reviewer for different journals (https://publons.com/author/1268786/). \nCurrently, Dr. Nawaz is working on stem cell-derived exosomes in tissue repair and regenerative medicine and using exosomes as RNA delivery vehicles and Drug Delivery (siRNA, RNAi, and mRNA based therapy).",institutionString:"University of Gothenburg",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Sao Paulo",institutionURL:null,country:{name:"Brazil"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"6",title:"Biochemistry, Genetics and Molecular Biology",slug:"biochemistry-genetics-and-molecular-biology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"286446",firstName:"Sara",lastName:"Bacvarova",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/286446/images/8491_n.jpg",email:"sara.b@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"69156",title:"Nurse-Patient Conflict: Verification of Structural Model",doi:"10.5772/intechopen.89130",slug:"nurse-patient-conflict-verification-of-structural-model",body:'A service is characterized by “intangibles,” “simultaneity of production and consumption,” “equivalent importance of the results and process” and “co-production with customers.” The types of services include “core service,” which is at the core of a service product, “sub-service,” which is associated with the core service, “contingent service,” which adapts to the situation, and “potential service element,” which is sought out by customers [1]. Subservice, which does not reflect on customer service at hotels and costs at hospitals, tends to be emphasized in service quality evaluation more so than the core service, including the provision of technology that reflects on costs [2]. Quality service is dependent on the subjective and objective evaluation of customers. Customer satisfaction with regard to service is associated with emotion, which impacts evaluation over time [3]. According to Simomura [4], emotion is a central concept in consumption behavior, and satisfaction with a service and customers’ emotions cannot be discussed separately. With respect to customer demand and quality, good quality as perceived by a customer is meeting the customer’s demand [5], as well as having a certain level of high knowledge, sensitivity, and values to create a better service [6].
Parasuraman et al.’s [7] SERVQUAL Instrument (a Multiple-item Scale for Measuring Service Quality) is most widely used for measuring a service based on the difference between expectations and satisfaction [8]. This instrument can measure not only customer expectations but also their perception of the quality of service that they received [9]. The perception of quality by service recipients is associated with the morale of the service providers and corporate spirit [10, 11]. We must know and understand the expectations of patients to measure quality of health care. In service marketing research, the relation between expectations for a service and perception of the service received is drawing attention [7, 10, 12, 13, 14]. Parasuraman et al. [15] evaluated SERVQUAL Instrument (a Multiple-item Scale for Measuring Service Quality), which they reported in 1985, based on psychological diagnosis. Accordingly, SERVQUAL for patient satisfaction with nursing care, namely, SERVQUAL-N, which is a modified version of SERVQUAL for nursing care, was developed [16]. Consequently, service evaluation based on SERVQUAL has been conducted in Europe, North America, and Asia [17, 18, 19, 20, 21, 22]. In SERVQUAL, service quality comprises elements of reliability, responsiveness, assurance, empathy, and tangibles. Meanwhile, Shanaki et al. [23] described the effects of empathy toward service quality using tangibles, responsiveness, trust, accessibility, and service recovery. This shows continuous development in research in various academic fields.
A nurse must perceive the feelings and emotions of a patient and respond appropriately so that the latter recognizes that he/she is receiving high quality health care. Nurse-patient conflict arises when a patient’s expectations are not met and trust is not established. It is ideal for the conflict to be resolved between a nurse and a patient. Patients have feelings that they are not able to tell nurses about, from which a potential conflict can arise. Patients suffer in situations where they perceive conflict, but they are unable to bring it up with the nurses because of reluctance or resignation. Because a patient’s perception affects quality evaluation of nursing care, this study focused on nurse-patient conflict and found meaning in understanding nurses’ and patients’ perception of phenomena. In the field of nursing care, consideration of patients’ emotions and response to their feelings have been considered important. To improve quality of nursing care, nurses are required to go beyond the superficial interaction with patients and respond in a way that is backed by academic significance. Patients’ evaluation is indispensable to quality nursing care. There is sufficient need for recognizing the fact that patients carry chaotic feelings, which, in turn, must be comprehended to be able to verbalize, document, conceptualize, and generalize such phenomenon. Therefore, this study is significant in that it academically focused on a phenomenon that has been overlooked thus far.
In general, various elements, including technical factors, interpersonal factors, cost, and environmental factors, influence patient satisfaction. As such, measuring patient satisfaction in diverse scenes of nursing care is a complex task [24, 25, 26, 27]. Patient satisfaction is recognized as an important index for service quality [19, 28, 29]. There is a positive correlation between patient satisfaction regarding nursing care and a patient’s perception of service quality [30]. There is also a strong correlation between satisfaction with nursing care and general satisfaction [31]. All nursing care activities are associated with a patient’s perception of patient satisfaction [32]. Moreover, values regarding patient satisfaction continue to evolve with time [33]. Oxler [34] focused on patient dissatisfaction and reported that commitment on the part of top leaders and staff was required to set aside time for understanding patient needs, thereby resolving complaints from patients and enhancing satisfaction.
In a study on patient satisfaction in nursing care, Abdellah and Levine [35] reported on patient satisfaction and occupational satisfaction of nurses. Risser [36] developed the Patient Satisfaction Scale (PSS) for measuring patient satisfaction with primary care nurses and nursing care. Research has advanced, starting with the analysis of the “patient satisfaction” concept regarding modern nursing care [37], incorporation of outpatients’ perception into the definition of nursing quality, demonstration of a NEdSERV quality model and development of a scale for service quality in nursing education [38]. These research activities led to the development of a patient-oriented scale for measuring service quality in the outpatient department [39]. In a survey conducted with patients awaiting discharge from the surgical ward of a teaching hospital in Taiwan, a primary care nurse’s years of experience as a nurse was found to have affected patient satisfaction [40]. Studies have reported the necessity of an examination focusing on new care models, a partnership care delivery model/core concepts and new models [41], an analysis of patient satisfaction with nursing care using a conceptual nursing framework [33], the development of a satisfaction scale for local nursing care [42], a gap model of care quality in patient-centered nursing care for elucidating concepts of patient-centered care [43], and the development of a scale for measuring satisfaction of critically ill patients [44].
Henderson [45] described her way of understating patients as “getting inside his/her skin,” and indicated that nurses should discern the needs of patients before providing nursing care. In the beginning of Interpersonal Aspects of Nursing by Travelbee (1971), Ruth Johnston’s (American Journal of Nursing 1971) “Listen, Nurse” was used to emphasize the interpersonal relation that transcends the positions of a nurse and patient. Peplau [46] demonstrated the importance in the encounter between a nurse and a patient and reported that a moral encounter that conveys the understanding of a patient’s vulnerability is important. Watson [47] showed that the nurse-patient relationship in nursing science contains intersubjective care and that its practice and process become transpersonal and metaphysical. Reported that a closer relationship is established between a nurse and a patient by shifting the nursing care perspective from organizational goals to patient-centered care (PCC). Cignel [48] considered compassion as an important concept in nurse-patient relationship and argued that compassion as the answer to suffering, which is at the center of care, is equivalent to high-quality care in today’s medical care. Described the influence of nurse-patient relationship by stating that the technique used by nurses to draw resources in managing patients, by involving themselves in a patient’s phenomenon and distancing themselves, attenuate their suffering that have become involved, but it may keep them from using resources and possibilities gained through interaction with patients. Stated that there is an interrelation within a social relationship, which is characterized by a complementary relationship through self-care based on an existing contractual relationship; Orem said that an ideal relationship would be one in which a patient’s and his/her family’s stress is reduced and would help them manage matters related to health and health care with a sense of responsibility.
High-quality nursing care is based on trust between nurses and patients. The word “trust” is derived from an old term used to express fidelity and loyalty; this fact has a long history [49]. It is difficult to clearly define nurse-patient trust based on literature [50, 51, 52]. Reported that a patient’s trust in a nurse is a necessary element for establishing a connection between the patient and that nurse.
Despite the lack of a clear definition of trust, trust affects whether a patient accepts care and treatment [53, 54, 55] and is an important factor in a nurse-patient relationship [51, 56]. Johns [57] suggested medical benefits, vulnerability, dependency, and participation in a care plan as being part of a conceptual framework of nurse-patient trust. Meanwhile, Belcher [58] stated that nurses need to act as good communicators to establish a close relationship with a patient while building trust.
In the 1950s, various nursing theories by nursing theorists were published in countries, including the United States. Starting with “Interpersonal relations in nursing” by Peplau [59] and the “Textbook of the principles and practice of nursing” by Harmer and Henderson [60], Johnson [61] argued that nursing requires care that must be provided by nurses to patients. Subsequently, nursing was considered as being based on interpersonal and personal relationships [62, 63]. As a result, mutual relationship drew attention. After Meyeroff’s [64] report on caring was published, caring drew attention in the 1970s. Human caring has been referred as concern and respect for others [65]. Considered caring as the heart and soul of nursing from the viewpoint of the diversity and universality of cultural care. Watson [47] placed nursing in relation to metaphysics and indicated that care is the essence of nursing; she also noted that caring is able to utilize humanity as common sense in intersubjective interaction as defined by phenomenology while suggesting an interrelationship between souls. Based on theorists’ conceptual analyses of caring, Morse et al. [66] classified caring into the following five categories: (1) caring as a human state (Lininger et al.), (2) caring as an affect (Babes), (3) caring as a moral imperative or ideal (Watson et al.), (4) caring as an interpersonal relationship (Gardo et al.), and (5) caring as a nursing intervention (Brown et al.). Therefore, in the 1960s and the 1970s, the nomenclature of primary phenomena in nursing science was established because of the clear need for detaching nursing from practice based on medical models [45, 67, 68]; (Rogers, 1970). Nursing concepts in Japan have been affected by claims of theorists who underwent these changes. The theory of human caring became widely known in Japan when Watson visited the country around 1990. Human care, whose main focus is on transpersonal care, has a high affinity with the spiritual culture of the East, and it appears to have been accepted as the essence of universal nursing care.
Around 2000, the importance of evidence-based practice (EBP) for high quality nursing was emphasized. It was defined as an important perspective for nurses when taking action as a professional [69, 70, 71, 72]. Sackett et al. [71] pointed out that EBP did not contain the opinions and decision-making of patients along with scientific evidence.
Patient centered care (PCC), along with nurse-patient relationship, was considered the basis for nursing care. PCC drew universal attention as being a form of active nursing intervention including sympathy and empathy [73, 74, 75]. Sidani [76] defined PCC as the provision of excellent service and improvement of quality patient care. Meanwhile, the Agency for Healthcare Research and Quality (AHRQ 2001) stated that placing an emphasis on PCC improves the quality of interaction between patients and health care providers and empowers patients in the process. EBP and PCC do not conflict one another and should not be considered separately. Burman [77] emphasized that EBP is among the cornerstones for providing better nursing care to patients. Burman also noted that the integration of EBP and PCC is essential for the health management of patients and the cultivation of organizational culture by nurses and other highly motivated clinicians to provide interdisciplinary PCC is required.
The term empathy was used by Robert Vischer, a German psychologist, in 1873. It was derived from the German word Einfühlung. It was born from the esthetics of the time, which belonged to psychology that considered the empirical/aesthetical/psychological aspects as important [78]. Empathy is the ability to share others’ thoughts and emotions [79]. It facilitates proactive behavior toward others and promotes social interaction as well as tolerant relationships. It is cultivated through time-dependent change as a person undergoes the developmental process. This ability appears in early childhood, develops in complex form from school age to adolescence (Eisenberg et al., 2002) [80], and continues from adulthood to old age [81, 82]. Empathy training facilitates the development of emotional abilities in school-age children, promotes skills and friendship [83], and enhances social conduct in adulthood [84]. The concept of empathy includes cognitive empathy, which allows one to sense the emotions of others and enables intentional thinking to a certain extent, and emotional empathy, which is accompanied by physical responses that are difficult to intentionally control [85, 86]. Gutsell and Inzlicht [87] described empathy from three perspectives: behavioral empathy, physical empathy, and subjective empathy.
Research on empathy has a long history in disciplines, such as psychology and sociology. In nursing science, research has been conducted based on these academic backgrounds. Empathy has been considered as a primary basic concept in nurse-patient relationships and nursing practice. Ens [88] defined empathy as a complex part of the concept of countertransference, whereas Roger [89] argued that countertransference is an inevitable factor in a nurse-patient relationship. Scott [90] maintained that empathy is based on moral perception. Empathy is said to be a technique developed for counseling in the field of psychology [91]. However, Nightingale had used “sympathy” to refer to nurse-patient relationships before the term empathy was used. The reasoning that “nurses must be kind and sympathetic at all times, but they should never be emotional” is based on the recognition that this quality as a nurse assists the treatment process in a nurse-patient relationship [59]. Olso [92] found that there was a correlation between empathy shown by nurses and quality of nursing care. Erikson [93] defined empathy as the ability to show concern for suffering and demonstrated that nurses are required to perceive the suffering of patients so that the latter are able to feel their human dignity being maintained. Erikson [94] stated that nurses must find the desires, trust, hope, powerlessness, guilt, and shame of patients to alleviate the latter’s suffering and must understand each patient’s unique experience with, knowledge of, and way of feeling toward his/her disease [93, 95]. Hence, empathy can be said to be the basis of therapeutic relationships in nurse-patient relationships.
Suffering refers to feelings and emotions necessary for those with disease, disability, and life issues to live, which form their experiences. For instance, this includes a diagnosis before birth made possible with medical advances, congenital disorders, chronic diseases, mental illnesses, and situations in which death is impending [63, 96]. According to Frankl [97], who is a psychiatrist heavily influenced by Freud and Adler, suffering is not something that one is born with but rather something one acquires. This is expressed as the “ability to suffer” and some consider that suffering cannot even be acquired if one is emotionless. Travelbee [63] stated that suffering, as with a disease, is an everyday life experience that befalls anyone and defines a status where an individual encounters suffering and experiences suffering at its worst as a malignant phase of despair non-caring and the terminal phase of apathetic indifference. Kato (2004) described suffering from a philosophical/ethical standpoint as primary and secondary suffering. Primary suffering is the anguish/suffering of those that seek help, whereas secondary suffering is suffering caused by a lack of response, inappropriate response, or failure/injustice/malice inherent in the action of responding.
Travelbee [63] suggested that suffering is accompanied by caring, that vulnerability to suffering is related to the ability range and depth of caring, and that the lack of caring ability induces strong suffering. This means that nurses attempt to truly understand the experiences and feelings unique to a patient [93, 95]. Mayeroff [98] stated that caring practice is formed when those involved share time and place by “being together” and “living together,” and emphasized the continuous relationship between the two. Ukigaya [99] indicated that nurses are also cared for by patients and that care has a bi-directional effect. Studies on patients’ suffering and nursing care must show that nurses are prepared to identify the suffering of patients for them to feel that their dignity is honored.
Various studies on critical life situations, mental problems, and end-of-life suffering have been conducted. However, no study focuses on patients’ emotions (secondary suffering) and shows that nursing (service) is no other than engaging with them.
Conflict research has long been conducted in the fields of, among others, psychology and sociology. Robbins [100] defined conflict as a process that starts when one perceives that others have exerted or are attempting to exert a negative effect on matters he/she considers important. No other problems are as strongly connected to emotion as when a conflict arises in interpersonal relationships and emotional changes accompany the occurrence of a conflict. In other words, Robbins stated that conflicts cannot be resolved effectively if one disregards the emotional element of a conflict and attempts to resolve them based on rationality and logic.
Marquis and Huston [101] defined conflict as arising from differences in values, expectations, and backgrounds. They suggested that “cultivation of a mutual relationship and sharing of understanding” are required for patients and medical professionals to maintain a positive relationship. They and stated that conflict arises when the personal relationship is no longer smoothly maintained [102]. Reports on patients’ specific situations, difficult patients [103], acute psychiatric wards [104], comparison of home care and nursing homes for older adults [105], and ways to respond to a conflict in specific scenes have been published in clinical conflict research since 2005. Nurses tend to use mutual dialog instead of engaging in a conflict in a stern manner to resolve conflicts in nursing situations [106]. Nurse-patient relationship is fundamental in partnership in nursing and interaction is required to maintain a positive relationship [107].
Conflict: In this study, conflict does not refer to evidential conflicts (e.g., medical disputes), but rather to nurse-patient mood discrepancies and emotions.
We explained to all eligible participants that the data obtained in this study would not be used to identify any individuals or used outside of this study; further, it would be strictly managed and destroyed upon completion of the study.
Furthermore, we explained to the nurses that participation was voluntary, refusal to participate would not be disadvantageous to them in any way, participation had no relationship with their course evaluation, and we would consider their submission of the survey form as their having consented to participate.
By contrast, in our explanation to the phone counselors, we assured them that participation in the interview was voluntary, had no relationship with their company performance evaluation, and they could rescind their consent to participate at any time. We obtained permission to use the existing data from the copyright holders.
This study was conducted under the approval of our institution’s research ethics committee.
As shown in the literature review, when a person makes some kind of value judgment, the emotion associated with the service received rather than the actual service received or the fact that he/she received the service affects the evaluation. Customer response to a service has been researched and systematized in business administration as direct purchasing and consumer choice behaviors. In the medical field, efforts have been made to adapt customer satisfaction and consumer choice behavior, which have been systematized in business administration, to clinical practice.
The focus of the present study is everyday nursing settings in which patients are in a specific (non-critical) situation. A patient suffers when he/she senses that a nurse regards his/her existential value lightly. A patient’s anguish/suffering constitutes primary suffering; secondary suffering is caused by a nurse’s lack of response to the primary suffering or a nurse’s inappropriate response or when failure/injustice/malice is inherent in a nurse’s action of responding. In the present study, I focused on nurse-patient conflict to understand patients’ suffering and nurses’ and patients’ perception of suffering. The reason this study focused on conflict is that a conflict is caused by emotional differences resulting from changes in the nurse-patient relationship. There is no study that focuses on the perception of patients, who are the service receivers, and bi-directionally examines the perception of nurses and patients with a focus on the sensing of emotional fluctuations and thoughts. Therefore, in this study, patients’ unspoken thoughts were verbalized and a conceptual model for phenomena, which have been overlooked by focusing on nurse-patient conflict in medical treatment settings, was constructed.
Stages 1–4 of Robbins’ [100] framework for the conflict process was applied as follows to nurse-patient conflicts in nursing settings where patients’ status was non-critical.
Stage 1 (potential opposition): elements latent in the occurrence of a conflict.
Stage 2 (cognition and personalization): scenes in which a conflict occurs <Recognition>.
Stage 3 (behavior): response (in expectation of problems).
Stage 4 (outcomes): outcomes (of a successfully maintained/built positive relationship).
The present study focused on areas that have been overlooked in everyday nursing scenes in which engaging with the depressing feelings of patients arising in nurse-patient relationships is not recognized as nursing. To understand the circumstances that have been overlooked, the present study focused on nurse-patient conflict and aimed to understand phenomena from the perspective of both nurses and patients and to establish a conceptual model.
Nurses
For a descriptive survey on nurses, this study involved 320 nurses that participated in a nursing manager workshop organized by a local nursing professional association in Japan. The reason for the selection was that they had gained appropriate nursing experience as a manager and that their experiences could be verbalized.
Telephone counselors (patients’ end)
For a survey on patients, because it was difficult to obtain data by interviewing patients directly in line with the intent of the present study, we interviewed eight telephone counselors. Telephone counselors belong to an incorporated non-profit organization whose members comprise non-medical professionals located in Osaka Prefecture, Japan. The organization provides consultations geared toward people for patients with feelings that they were not able to convey to medical professionals.
Nurses
In the descriptive survey on nurses, they were instructed to recall nurse-patient conflicts and describe them. Age and years of nursing experience at the time of conflict were recorded as personal characteristics.
Telephone counselors (patients)
In the interviews with telephone counselors, they were instructed to recall consultations regarding nurse-patient conflicts. It was confirmed that existing data could be organized in a similar structure to data obtained through the interviews. With regard to personal characteristics, we referred to the age (age range) of patients who called in for a consultation and telephone counseling history of the telephone counselors.
In the descriptive survey on nurses, 72 scenes were subjected to analysis after 72 scenes were collected and evaluated to determine whether they were in line with the intent of the present study. In the interviews with telephone counselors, verbatim records of all the interviews were made, and 72 scenes were subjected to analysis.
When a conflict arose, systematic thinking, including logical thinking based on EBP and empathic understanding of patients based on PCC, was observed in nurses. Meanwhile, patients carried fragmented emotions, such as “anxiety,” “sorrow,” “dejection,” and “anger.” In other words, when I simultaneously looked at the perception of nurses and patients, there was a gap in perception, which was observed as “nurses’ systematic understanding” and “patients’ fragmented emotions.”
After looking at the perception of nurses and patients simultaneously, we found that there was a gap observed as “nurses’ systematic understanding” and “patients’ fragmented emotions.” When a nurse recognizes this gap in perception, a nurse senses the fragmented emotions that a patient carries while engaging in systematic thinking and understanding. Alternatively, the gap was naturally filled by the nurse placing himself/herself in the patient’s shoes to understand the latter’s emotions, then a positive interaction would be observed when the nurse expressed empathic understanding toward the patient and shared his/her suffering.
In Study 1, we showed that the empathic attitude of a nurse, who recognized the gap between the nurse and patient, resonated with the patient at a soul level. This resulted in a positive interaction where the gap in perception between the nurse and patient was recognized, enabling emotional exchange. Building on these findings, I constructed a model for suffering based on the gap in perception between nurses and patients, and positive interaction (Figure 1).
Suffering based on the gap in perception between a nurse and a patient, and a positive interaction model.
The perception and cognition of phenomena that occur in nursing settings differ between nurses and patients. Nurses encounter various situations related to patients’ life and death and experience emotional fluctuations associated with them on a daily basis. Meanwhile, life change caused by hospitalization, although it may be for a short period, is a once, if not only a few times, in a lifetime experience for the patients. As such, because nurses and patients are in different positions, they have different ways of understanding a phenomenon and standards of perception. I elucidated this difference as a gap. Based on what has been described, suffering experienced by a patient was defined as primary suffering. With regard to primary suffering, if the nurse does not recognize conflict and the gap that causes it, the patient will notice the nurse’s lack of awareness of it. In other words, the patient experiences secondary suffering when he/she instinctively and intuitively senses the nurse is not truly willing to help the patient who is experiencing primary suffering. As a result, the patient suffers even more, giving rise to distrust in medical care, interfering with his/her health behavior.
If the nurse adequately understands the gap that caused the conflict and comes to feel the emotions of the patient unintentionally and in a natural way, emotional exchange takes place; this cultivates a positive interaction. This process is considered the “process by which the patient’s mind is adjusted.”
Nurses interact with patients at a more intimate level than other health care workers and are committed to life-threatening moments and important life events. As such, nurses have more opportunities to obtain information about patients. Excess and insufficient information can cause conflict. Nurses also witness patients undergoing a great deal of emotional fluctuations. However, they are anxious because they feel that they may no longer be able to engage in “nursing work” if they accept patients’ emotions as they are. Washida [108] described such situation as the critical point in clinical practice and where the patients suffer. In several ways, nurses are unable to put it together unless they become objective and distance themselves from emotional fluctuations. It may be that they are able to continue “nursing work” by unconsciously numbing their emotions. The data have shown that conflict is attributable to the gap between nurses and patients.
The data of the present study was obtained by applying Robbins’s [100] framework for conflict process. Nurse-patient communication and trust are believed to be involved in potential opposition. As Usui [109] stated, laypeople remain in a limited understanding of superficial phenomena, whereas experts can penetrate the internal structure of the subject with the help of expert knowledge. Nursing professionals are able to and are expected to enter into a patient’s inner state and respond accordingly. However, when nurses are unable to meet these expectations, secondary suffering arises, and patients experience even more anguish.
Perception of nurses and patients caused by conflict.
There was a gap in perception between nurses and patients with regard to conflict. It was observed that nurses tended to understand phenomena using logical thinking, based on EBP, and empathic understanding, based on PCC. This is because nurses were trained as professionals and accustomed to understanding perceived phenomena using scientific thinking and grasping a patient’s feelings based on clinical experience. By contrast, patients, who had not received specialized education and whose physical condition had deteriorated, perceived and responded to phenomena with fragmented emotions. Therefore, there was a gap in the perception between nurses and patients. There appears to be a gap between the experience of nurses and patients as humans systematize their experiences and attempt to give them meaning ([89], p. 88).
Four aspects of nurse-patient perception gap.
There was a difference in perception between nurses and patients in situations where a conflict had arisen. There was a gap in communication between them in terms of communication for conveying their perception. In a nurse-patient relationship, communication is not only limited to the process of simply sending/receiving verbal or non-verbal messages but also includes a wider range of information [110]. A gap is created when one fails to receive the information sent. In addition, it has been suggested that communication aimed at ensuring quality of nursing helps develop a positive nurse-patient relationship [111, 112, 113]. Attention should also be paid to the relation between the two.
Nurses’ recognition of the perception gap.
There was a gap in perception between nurses and patients in situations where a conflict had arisen. Whether nurses recognize this gap affects the way they influence patients. Nurses will not give any thought to patients’ emotions unless they are aware of the gap. Recognizing the gap between nurses and patients is the first step in achieving true empathy.
In the present study, we also focused on the fact that patients come to experience an emotion because of conflict. Emotional exchange was defined as sending “emotional” messages to whom one feels safe to express “emotions” and share his/her emotional world as a result of them receiving those “emotional” messages as they are.
Nurses were able to notice and share patients’ anguish owing to the empathic interaction in which they recognized the gap with patients. Emotional intelligence (EI), which is the ability to sense patients’ emotions, on the nurses’ part is believed to be involved in the process. EI is the ability to understand emotion accurately, utilize emotion to facilitate recognition, and reflect on emotion [114], in addition to one’s own motivation and human relationship skills (Goleman 1995). EI was internationally acknowledged as a result of Goleman’s (1998) “Working with Emotional Intelligence.” Nurses, whose profession involves interaction with others, are required to have a high level of EI, particularly the ability to sense patients’ emotions and respond accordingly.
The word empathy was derived from the Greek word “empatheia,” which was formed by combining em (to attempt to insert) and patheia (suffering). The Oxford English Dictionary defines empathy as “the ability to project personality on the subject of reflection (and to perfectly understand it).” It is a term primarily related to the field of psychology.
We believe that feeling a patient’s feelings/intentions and standing by them are equal to showing an interest in his/her concerns. Nurses are equipped with not only the ability to logically understand matters but also the sensitivity to acknowledge the emotions patients experience as a person. Intentional empathy is often considered as the act of entering into others’ emotions [115]. To stand by the patients, it is key to interact with them while acknowledging the gap and for nurses to place themselves in the thoughts of patients.
Patients are in a state of distress, and they find the act of conveying the fact painful (suffering). Moreover, they suffer from the pain of not being empathized and understood. In short, their suffering is two-fold. Emotions of “anxiety,” “sorrow,” “dejection,” and “anger” experienced by patients constitute primary suffering; secondary suffering arises when they are unable to engage in emotional exchange with nurses [99]. Even if patients’ suffering is not resolved altogether when a conflict arises, showing concern for their suffering and approaching their wishes by coming from the same state are considered sharing of suffering. Nurses must show concern to patients’ emotions, which Nightingale [116] called the question about “the understanding of the things one is in the process of doing”; it is “the ability to put oneself in another person’s shoes, the ability to understand intuitively what that person needs, and the ability to take on the fate of that person.” These are unique to nursing.
In the present study, we focused on the mentally/physically non-critical situations of patients in which issues, such as patients’ depressive feelings that do not pose a medical or nursing problem, were not recognized as requiring nursing intervention and thus overlooked. The purpose of the study was to elucidate this concept.
Data showed that both experienced and newly recruited nurses with an active imagination had an intuition that “something was different about the patients,” or “something had happened,” or “something was wrong.” An “awakening” takes place when one intuitively grasps a patient and distances oneself from this understanding. How, then, is this possible? This is achieved by providing nursing care while caring for a patient and wishing to understand the inner state of that person, that is, “passion” exuding from a nurse’s personality that is beyond the technical limits of communication skills and empathic understanding. It may be technically possible for a nurse to perceive a gap and attempt to focus his/her mind on phenomena. However, to go a step further, techniques alone are not enough. Patients must be able to feel that they are fortunate to have met the nurse and are emotionally relieved. We were able to demonstrate that striving to be such a nurse results in high-quality nursing practice and shows the profundity of a practice involving humans.
“Passion” exuding from nurses is said to fall under the scope of nurses’ individual ability. This area has been regarded as part of personal capability and appeal. It has not been academically studied because of the lack of clear training methods or evaluation indices for exploring it. However, without considering the relationship with patients and giving thought to this area, true improvement of quality as perceivable by patients is not possible. I was able to suggest the need for academic inquiry by the model of the present study.
We explained the purpose/results of the present study and the final model to clinicians to ask for their opinions and examine the validity of the model. We asked for the opinions of three individuals with 30–40 years of nursing experience, who understood the intent of the present study, and who previously worked in acute wards and currently belong to the field of visiting nursing care.
First, it should come as no surprise that the relationship with patients does not deepen by examining the horizontal line (the flow from primary to secondary suffering) of the model. In fact, we visited patients who experienced secondary suffering as visiting nurses. Therefore, it was approved that nurses’ involvement with primary suffering was important based on the opinion that “a patient may not have been so stubborn if the nurses had engaged at a slightly deeper level during the hospitalization period.” Next, based on the examination of the vertical line (the flow from primary suffering to positive interaction), it was agreed upon that in some cases, a positive encounter with a nurse may be more important than curing the disease itself. In recent years, being able to engage in emotional exchange with nurses provides a positive interaction experience for those who are more than likely to have no one close-by to understand them, as an extremely large number of patients are living with chronic diseases and family morphology changes as they age. Consequently, clinicians endorsed the validity of the model. It was shown that there is a need to recognize this study’s model in and its possible contribution to clinical practice. Therefore, I believe that the model created in this study represents everyday scenes for nurses and patients and is useful for reaffirming the fact that it was overlooked and not recognized.
Nurse-patient relationship as a result of nurse-patient conflict depends on the way one looks at “communication” and “trust.” Its interaction may involve drawing strength from patients as the power of nursing. It was shown that sharing of suffering by emotional exchange was a key concept for it. Washida [108] stated that the relationship between those being admitted and those accepting them is reversed in hospitals. Washida added that clinical settings are the critical plane on which those receiving care and those providing care come in contact in an inverted manner. The nurses working there become partly exhausted because of work responsibilities and the physical demands of work, but more so because they experience extreme emotional fluctuations multiple times a day. These emotional fluctuations rarely happen to average people. Amid these fluctuations, nurses are believed to maintain their balance by unconsciously getting out of touch with patients’ myriad emotions and feelings while using scientific thinking at all times to avoid being affected by these fluctuations. With regard to the difficulty in listening, Kawai et al. (2003, p. 211) stated that “narrative does not trickle down in front of those who look for narrative, while it reveals itself only a little to those who patiently wait for it.” Kawai and colleagues explained: “unless one is convinced that others will accept whatever he/she says and that they will follow through with the various problems that may arise as a result of him/her speaking out, he/she will not speak about the entangled thoughts he/she has. To speak means one becomes multiplexed in front of others and will unstably float around with no visible landing point.” Patients suffering from a disease have a heightened sensitivity. They are probably able to intuitively sense whether nurses that are taking care of them are mature on the inside. What is important to patients is that nurses make an earnest effort to engage with them. They are pleased with this effort, and they perhaps do not expect nurses to completely understand them, the patients who are in great distress.
Partial additions and modifications were made to my dissertation for the doctoral program at Osaka University Graduate School in the present study.
Since the discovery of induced pluripotent stem cells (iPSCs) by Yamanaka and Takahashi in 2006, many expectations have emerged, and iPSCs have opened up a world of possibilities for new cell-based therapies in regenerative medicine [1]. In the domain of pluripotent stem cells, iPSCs are considered as equivalent to embryonic stem cells (ESCs), because of two intrinsic key properties: their indefinite proliferative capacities while preserving pluripotency and their capacity to differentiate into all known cell types. However, in contrast to ESCs, iPSCs can be generated without any controversial ethical issues, thus favoring their use in clinical settings. Last but not least, in an autologous approach of cell-based therapy, by using the patient’s own cells as source for iPSC generation, one circumvents all the issues related to the immunological compatibility between the donor and receiver. This largely explains the tremendous enthusiasm engendered by iPSC discovery in the sphere of regenerative medicine during the last decade. In this review article, we provide an overview of the launched clinical trials with iPSC and the ongoing efforts to understand the risk related to safety of iPSC-derived cells, highlighting some of the problems that have to be overcome.
After over a decade of research on iPSC, and due to fast-track facilitating procedure in Japan, several clinical studies were launched. While the first clinical trial based on the human ESC started in 2010, taking advantage of the acquired extensive knowledge of ESC biology, despite their relatively recent discovery, the first clinical study based on the iPSC-derived retinal pigmented epithelium was authorized and conducted at the RIKEN Institute in Japan in 2014 [2]. A sheet of autologous iPSC-derived retinal cells were transplanted in a patient with eye-related macular degeneration (AMD). In 2015, the RIKEN Institute decided to suspend the study due to safety concerns on the cells of the second recruited patient [3]. Nonetheless, regarding the first transplanted patient, a 25-month follow-up revealed neither serious events, nor clinical signs of rejection. Moreover, the macular degeneration progress was delayed in the treated eye compared to the untreated eye. This result corroborated all the results obtained previously in the course of the ESC-based clinical studies, where no adverse events related to transplanted cells were observed. Still this problem induced a shift in the approach from patient-specific autologous to highly securized allogeneic iPSC lines. This study was resumed in 2017 and until now five patients with AMD have been treated with allogeneic iPSC-derived cells.
Since then, several clinical studies based on allogeneic iPSCs have been developed and approved. Until mid-2019, there have been nine ongoing clinical studies based on iPSC, mostly nationally approved in Japan, with four of them being approved in the first months of 2019, with indications including Parkinson’s disease, AMD, severe cardiac failure, aplastic anemia, spinal cord injury and corneal stem cell deficiency. Furthermore, two private companies—Cynata Therapeutics, an Australian stem cell and regenerative medicine company, and Fate Therapeutics, an American clinical-stage biopharmaceutical company—have developed a line of products based on allogeneic human iPSC-derived cells. In Australia and United Kingdom, Cynata Therapeutics just concluded a phase I study using CYP-001, an iPSC-derived mesenchymoangioblast precursor administered intravenously in 15 patients with graft-versus-host disease (GVHD) occurring after an allogeneic hematopoietic stem cell transplant [4]. Currently, all patients treated so far have demonstrated at least a partial response, while no treatment-related serious adverse events or safety concerns have been observed. The product development activities of CYP-001 will be done in a phase II study in 2019 by Fujifilm in collaboration with Cynata Therapeutics. On its part, Fate Therapeutics received a first approval from Food and Drug Administration (FDA) in November 2018 to transplant an off-the-shelf iPSC-derived Natural Killer cell, FT-500, as cancer immunotherapy to treat solid tumors and for a second cell product derived from a genetically engineered iPSC, FT-516, in February 2019, for the treatment of relapsed/refractory hematologic malignancies. For the first product FT-500, all the three patients with advanced solid tumors have been treated with multiple doses of FT-500, 100 million cells per dose, and it has been well tolerated with no dose-limiting toxicities or adverse events [5].
Even though the first clinical studies have already been started, technical advances in iPSC biology have revealed that several factors could affect their safety for a larger range of medical applications, and should be taken into account for short- and long-term follow-up of patients. Two of the major concerns related to iPSC-based products are their potential tumorigenicity and immunogenicity. The scientific community is still continuing to elucidate the biological mechanisms underlying iPSC’s immunogenicity and tumorigenicity and how to manage or overcome them.
The potential risk of tumorigenicity to patients from both teratomas and malignant tumors could arise if transplanted cells are contaminated with undifferentiated iPSC, or if transplanted cells have been genetically modified and become unstable during the in vitro production steps.
The major concern related to iPSC-based tumorigenicity is the reprogramming method. In the original cocktail of transcription factors developed by Yamanaka, somatic cells are transduced by retroviral vectors that become integrated into the genome of the host cells. Two of these factors—c-Myc and klf4—are potent oncogenes [6]. Subsequently, reports of tumorigenicity after transplantation of iPSC or iPSC-derived cells are not surprising. Thereby, teratoma formation could be induced by the undesired activation/suppression of essential host genes proximal to integration sites or by residual expression of reprogramming factors in the derived cells in animal model [7, 8]. With hindsight, there is evidence for the necessity to select a non-integrative method for reprogramming, a higher rate of genomic alterations occurring when human iPSCs are generated with viral vectors, compared to mRNA [7, 9]. Numerous studies, focused on the choice of reprogramming factors and methods of delivery, have developed various novel strategies to enhance the efficiency of reprogramming and reduce the potential risk of tumorigenicity. To circumvent this risk, human iPSCs have been generated by several “integration-free” methods, based on the use of viral vectors (adenoviral vectors and Sendai virus-based vectors) or non-viral vectors (piggyBac system, minicircle vector, and episomal vectors). Originally, the four transcription factors needed for complete cell reprograming were c-myc, klf4, oct4 and sox2 [1]. The pro-tumorigenic transcription factor c-myc has been found to be unnecessary for the reprogramming process, but the overall efficiency is decreased without it. Several strategies have been developed with the use of different transcription factors and/or replacement of c-myc, or the use of direct protein delivery and synthesized mRNA [10, 11, 12].
Furthermore, the tumorigenicity risk is often linked to the genetic instability of iPSC. Random genomic alterations are frequently observed in human iPSCs showing their intrinsic instability, essentially due to the massive genome remodeling, and probably also resulting from various mechanisms such as replicative stress, reactivation of the telomerase and metabolism modification from the oxidative to the glycolytic state. Epigenetic modifications may also contribute to iPSC variation due to residual epigenetic memories of the starting cell type [13]. The incomplete resetting of the non-CpG methylation patterns during reprogramming leads to a biased differential potential in certain cell types depending on the donor cell source [14, 15]. However, it has been shown that their residual epigenetic memory diminishes with the in vitro expansion over a period of time [16, 17]. As just mentioned, the selection of the donor cell type is of importance. Many human somatic cell types have been successfully reprogrammed. However, even if the use of different transcription factors, delivery methods and culture conditions does not facilitate any comparison, it is well known that reprogramming efficiencies, kinetics and tumorigenicity vary between somatic cell types. Firstly, cell sources have to be permissive to avoid to turn to integrative methods and to the use of oncogenes. Some human, adult somatic cells, such as melanocytes, are known to naturally express endogenously reprogramming factors, for instance Sox 2, at sufficiently high levels [18, 19]. Moreover, some types of donor cells such as dermal fibroblasts and blood cells are easily accessible, but they might carry more mutational burdens and chromosomal abnormalities, due to their frequent exposure to environmental stress factors, like ultraviolet rays, or due to the donor’s age, thereby leading to increased tumorigenicity, and significant safety problems [20, 21]. With all these considerations of cell variability and tumorigenic potential in mind, reflection on the generation of homogeneous cell source and banking emerged.
Many approaches have been evaluated to address the tumorigenicity challenge by eliminating the pluripotent cells of the final product such as small molecule, genetic approach to introduce a suicide gene; miRNA switch; antibodies targeting a surface-specific antigen; phototoxic approach; live detection and quantification of the residual human iPSC [22]. For the suicide gene approach, the most widely used gene is herpes simplex virus thymidine kinase (HSV-TK) that phosphorylates ganciclovir (GCV) and induces apoptosis by inhibiting DNA synthesis. Many studies demonstrated its efficacy as safeguard to eliminate tumoral cells [23]. Until then, this genetic approach with an inducible suicide system may remain not necessary enough to induce tumor elimination because of potential acquired resistance to GCV due to variability of insertion location sites and to the uncontrolled number of inserted transgene [24]. Another study demonstrated the same mechanism of inducing apoptosis in 95% of iPSCs and iPSC-derived cells by transducing an inducible Caspase 9 [25]. Recently, with development of targeted genetic strategies such as gene-editing, researchers try to identify the location of “genomic safe harbors” (GSH), corresponding to the safest permissive loci for transgenes’ insertion [26]. The already known GSH candidates could be AAVS1 (adeno-associated virus integration site 1), CCR5 (chemokine CC motif receptor 5), human ROSA26 and some extragenic loci. Recently, to predict the influence of gene integration on nearby genes, it has been suggested that the combination of several distinct approaches such as the analysis of the topologically associated domains of GSH candidates of chromosomes could reduce the risks associated with cell therapy [27]. Another targeted alternative, eliminating selectively residual pluripotent cells sparing precursors and differentiated cells, involves PluriSIns, pluripotent cells-specific inhibitors [28]. Alternatively, antibody, lectin or miRNA-mediated removal undesired cells were developed to suppress the pluripotent stem cells from the final product [29]. Lastly, a novel methodology using synthetic microRNA switch is developed to improve the purity of the final product even if the cell surface markers are not available to tag the relevant cells [30, 31].
The immunogenicity of differentiated cells derived from iPSC is of clinical significance. At the beginning, because of the use of the patient’s own cells, theoretically there is no risk of rejection after their transplantation. Some studies demonstrated no immune rejection of autologous iPSC-derived cells, but an activated immune response after the use of allogeneic iPS derived cells. Contrarily, immune rejection has been observed after autologous transplantation of iPSC-derived cells, suggesting that in vitro operations could also impact on the immunogenicity of the iPSC [32]. Moreover, the immune response to undifferentiated iPSC is different from their derivatives, emphasizing the need to perform similar comparative analyses in starting cell populations in order to predict immune tolerance after transplantation. Whereas autologous hiPSC-derived smooth muscle cells were highly immunogenic, autologous hiPSC-derived retinal pigment epithelial (RPE) cells were immune tolerated, suggesting a potential abnormal expression of some immunogenic antigens in smooth muscle cells [33]. These results demonstrated that the nature of the differentiated cells could trigger an immune response suggesting the importance of the differentiation protocol.
As mentioned earlier, because of their genomic instability, generation, amplification and differentiation of iPSC could induce a modified immune response of the iPSC in vivo. Concerning reprogramming, the RNA-based methods are relatively efficient and do not integrate in the genome, but they are also known to be highly immunogenic. Concerning cell type, it has been widely shown that iPSCs could be generated from a patient’s own cells including fat cells, nerve cells, skin fibroblasts, cuticle cells, fetal foreskin cells, B cells, T cells, peripheral blood mononuclear cells, umbilical cord mesenchymal cells, chorionic mesenchymal cells and amniotic mesenchymal cells. But, some studies showed that the genetic memory of the cellular immunogenicity is conserved after reprogramming and differentiation. So, the selection of donor cell type/origin is crucial. As an example, iPSCs derived from less immunogenic cells, such as umbilical cord mesenchymal cells, generated less immunogenic neural derivatives than those from skin fibroblasts-derived iPSCs [34]. Recently, several researchers showed the less immunogenic potential of some iPSC-derived cells as cartilage and retinal pigment epithelium cells when they are implanted in vivo, arguing that some cell types are less immunogenic and should be preferred for clinical settings [35, 36].
Recently, a novel approach of “Universal” iPSC was developed to address the difficulty of immunogenicity of allogeneic iPSCs. Hypoimmunogenicity of iPSC was induced by inactivation of major histocompatibility complex class I and II genes and overexpression of CD47 enabled them to escape to immune rejection in fully HLA-mismatched allogeneic recipients. This strategy allowed the long-term survival of the transplanted cells without the use of immunosuppression. However, overexpression of CD47 is associated with malignant transformation, leading to include some suicide strategies as a safety concern [37]. These immune escape approaches open the door to the clinical use of allogeneic iPSC-derived cell products without immune rejection concerns and complications. However, their complex production process including a combination of several transduction and gene-editing operations could add many safety issues. Even though other vectors and gene-editing techniques [38, 39] could also be used to reduce the risks, the multiple genetic manipulations and additional expansions in culture require a reinforced control of the “Universal” iPSC quality for clinical settings.
The use of human iPSCs in medicinal applications requires the establishment of standardized and validated protocols that will allow large-scale, cost-effective cultivation procedure, while maintaining their quality. Implementation of good manufacturing practice (GMP)-compliant protocols for the generation and maintenance of human iPSC lines is crucial to increase the application safety and to fulfill the regulatory requirements to obtain clinical trials’ approval. Many efforts to increase the overall iPSC stability, reproducibility and quality have been performed by (1) selecting the cell type that is easily accessible, less immunogenic, and permissive for reprogramming and presents the ability to be stored for longer periods of time; (2) improving reprogramming efficiency, which should be as high as possible without genomic integration-based delivery method and without using oncogene and (3) improving cultivation methods with xeno- and feeder-free products, with defined and scalable conditions for maintenance and differentiation of human iPSC such as automation, closed cell systems and validated protocols [40]. Moreover, selection of cell source is of importance. Demonstration of comparability, standardization and validation of such systems is critical for iPSC-derived therapies. To circumvent and manage the safety risk of the iPSC for regenerative medicine, several groups worked at the early stage on the development of standardized clinical grade iPSC banks from allogeneic donors. Indeed, the use of highly defined iPSC as starting cells presents many advantages as overcoming the genetic variations inducing different immunogenicity, genetic instability, tumorigenicity, and differentiation outcomes. Moreover, generation of iPSC from each patient is costly and time-consuming. In this regard, several groups in the world have developed banking of allogeneic iPSC lines for clinical use with validated and standardized protocols. The possibility of creating off-the-shelf iPSC-based therapies has attracted not only academics but also industrial groups as Lonzo and Cellular Dynamics International, a Fujifilm company.
iPSC banks can provide a cost-effective mass-production strategy. Several groups have developed iPSC banks from selected HLA donors trying to cover the majority of the population [41, 42]. The Center for iPSC Research and Application (CiRA), in Kyoto University, started the iPS Cell Stock for Regenerative Medicine in 2013. Initially, based on the limited diversity of the Japanese population, CiRA wanted to generate clinical-grade iPSCs from samples of peripheral blood and umbilical cord blood from healthy selected donors that would cover 90% of Japanese population with only 50 iPSC lines [43]. This strategy is valuable for countries such as Japan, but could be difficult to expand to the worldwide population. It has been evaluated that a multiethnic iPSC bank of the 100 most common HLA types in each population would cover only 78% of European individuals, 63% of Asians, 52% of Hispanics and 45% of African Americans [44]. This probabilistic model highlights the necessity of a large-scale international collaboration for the constitution of haplobank of iPSC lines. Using HLA-homozygous donors limits the numbers of iPSC lines needed to cover a given population, but identification of the potential donors would need large screenings or the use of established data from cord blood banks. The potential development of “universal” iPSCs made of genetically modified cells offering an off-the-shelf product that is readily available could be an alternative to the iPSC bank using materials from HLA-homozygous donors. The “universal” iPSC could solve the problem of immune rejection profile of iPSC-derived cells by artificially expressing, for example, HLA molecule as HLA-E allowing iPSC-derived cells to escape T cell-mediated rejection and to be resistant to NK-cell lysis [37, 45].
Nevertheless, stochastic events potentially occurring during reprogramming, colony expansion, iPSC selection, differentiation, iPSC-derived cell expansion and purification, storage and transport could complicate efforts toward a standardized product. Consequently, it has to be taken into consideration that variation may exist within any iPSC bank, between iPSC and final product composed of iPSC-derived cells in the clinic. Such variability requires continual extensive genotypic, phenotypic and functional assessment and highlights the need of a global quality control confirming the iPSC and the iPSC-derived cells’ quality whatever the manufacturer, the reprogramming method or the cell donors.
Given the high variability across iPSC lines and their differentiated derivatives in terms of their epigenetic status, tumorigenic and immunogenic potential, differentiation capacity, batch variability and existence of heterogeneous populations and/or non-relevant cells such as contaminating cell, the clinical outcome of the cell replacement therapy, in terms of efficacy and safety with these iPSC-based products, highly relies on the acceptable quality and safety standards of these products. Because of dissimilarities between institutions on these criteria, agreement on the critical quality attributes (CQAs) of such lines and the assays that should be used is required. The CQAs correspond to the chemical, physical and biological properties of the product. As well as the type of assay, they have to be defined within an appropriate limit, range or distribution to ensure quality and safety of the product. For cell therapy product and for clinical-grade iPSC, the CQAs include identity, microbiological sterility, genetic fidelity and stability, viability, characterization and potency. In the last few years, there was a common effort made on the banking and the quality control of the iPSC lines. After a series of workshop, adaptation to iPSC of the established recommendations and guidance realized by the International Stem Cell Banking Initiative (ISCBI) for human embryonic stem cell banking, has generated initial recommendations on the minimum dataset required to consider an iPSC line of clinical grade [46]. During these workshops, the researchers, industrial and regulation agencies pointed out the requirement of standardization and validation of process and quality and safety controls. For each criterion, one or several tests are required with regard to the recommended analytical methods. Global consensus recommends the performance of assays by accredited and licensed laboratories. When it is not available, in-house tests should be undertaken after validation and qualification, and comparability with other laboratories should be performed if possible.
The first mandatory test is to validate the identity of the iPSC line with the short tandem repeat (STR) analysis to genotype the original cells, the iPSC seeds and the master cell bank to ascertain the absence of switch or cross contamination of several iPSC lines during generation or maintenance process. Due to the nature of the stem cell-based products, they cannot be sterilized. The assessment of the microbiological sterility is of the highest importance and should be performed not only on the final product. This should include the mycoplasma, bacteriology and viral testing supplemented by endotoxins detection assay and should have a negative result. The genetic stability and fidelity of the iPSC lines should be evaluated by residual vector testing and karyotype. To eliminate the risk of potential cell transformation and the risk of malignancy development in patients, residual vector testing has to be ≤1 plasmid copy per 100 cells in seed and master cell banks and the karyotype should be normal on more than 20 metaphases. So far, techniques with high precision such as single nucleotide polymorphism (SNP) and whole genome analysis or other genetic markers are not required but could be performed for information. To give an appropriate dosage of cells, viability should be >60%. Calculation of doubling time and detection of cell debris are not required but could provide useful information. To manage the risk associated with the presence of non-desired or spontaneously differentiated cells, iPSCs have to be characterized by the expression of a minimum of two markers from the standard human pluripotent stem cells panel (positive for Oct4, TRA-1-60, TRA-1-81, SSEA-3, SSEA-4, Sox2, Nanog). A combination of one intracellular and one extracellular marker should be used and should be >70%. Finally, for the potency assay, reflecting the biological activity of the cells, embryoid body formation or directed differentiation of monolayer cultures to produce cell types representative of all three embryonic germ layers is mandatory. The teratoma formation in severe combined immune-deficient (SCiD) mouse injection assay is not mandatory for the iPSC due to a reproducibility problem, high cost and non-ethical procedure. Molecular pluripotency assays such as mRNA array- and RNA-Seq-based gene expression assays could be kept for information if they are performed molecular pluripotency assays such as mRNA array- and RNA-Seq-based gene expression assays could be for information but are not required. For the iPS-derived differentiated therapeutic products, the minimal criteria are mostly identical except for the phenotypical characterization, which should validate the absence of pluripotent stem cell markers, the expression of differentiation markers unique to the therapeutic product and assess 100% purity of the therapeutic cellular product without any contaminating other lineage cell types.
This consensus on CQA and minimum testing requirements for clinical-grade iPSC lines will evolve with the advances in scientific understanding and development in technology and best practices. The Global Alliance for iPSC Therapies (GAiT), which facilitates the development of general clinical-grade iPSC standards by community engagement and consensus building to support the global application of iPSC-derived cellular therapeutics, is in charge of the future evolution of the consensus on quality and safety standards required for a clinical-grade iPSC. Moreover, GAiT presents objectives to achieve consensus on donor selection and screening criteria and consent standards, which with future commercialization and global distribution also require ethical review.
It is quite remarkable that in just over 10 years, research using iPSC has led to several clinical studies, with many more applications expected to follow. In few years, the iPSC-based therapies induced a switch to a mass production of clinical-grade iPSC for the benefit of a large population at affordable costs, with the generation of clinical-grade iPSC banks, and with a stronger involvement of biopharmaceutical companies. This shift led to many efforts for the standardization of generation, maintenance and differentiation procedures, and for the establishment of quality and safety standards for the clinical-grade iPSC and their derivatives prior to transplantation to patients.
There are still a number of challenges that must be overcome for iPSCs to reach their full potential. The improvement of manufacturing procedures for a large-scale production would provide higher quality cells for clinical iPSC-based therapies. Quality and safety controls are also challenging. Predicting cancer risk based on sequence information is a formidable task, and failure to detect oncogenic mutations is not necessarily a warrantor of the non-tumorigenicity of iPSC-based products, suggesting that recommendations should still evolve with scientific advances.
Due to their large potential in regenerative medicine, such as the generation of complex 3D structures, tissues or organs, more challenges in differentiation protocols in 3D structures have to be overcome for the up-coming year, without compromising quality and safety of iPSCs.
The authors declare no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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\\n\\nFei Wei 2016-18
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\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
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