\r\n\tmolecular and imaging methods for detection and identification of plant diseases have many limitations that will be discussed in this book. This sparked interest in the development of minimally invasive and substrate general spectroscopic
\r\n\ttechniques that can be used directly in the field for confirmatory plant disease diagnostics.
\r\n\tThis book will also discuss recent progress in development of reflectance, infrared, Raman and surface-enhanced Raman
\r\n\tspectroscopy for detection and identification of plant diseases. It will also present advantages and disadvantages of these optical spectroscopy methods compared to the most common molecular and imaging techniques.
\r\n\tThe book also aims to discuss specific plant diseases, their symptoms and available methods of treatment.
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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"}}]},chapter:{item:{type:"chapter",id:"41913",title:"Quality of Life in Patients Undergoing Hemodialysis",doi:"10.5772/52277",slug:"quality-of-life-in-patients-undergoing-hemodialysis",body:'Quality of life (QoL) is a broad multidimensional concept that usually includes subjective evaluations of both positive and negative aspects of life [1]. What makes it challenging to measure is that, although the term “quality of life”has meaning for nearly everyone and every academic discipline, individuals and groups can define it differently. Philosophers were concerned with the nature of human existence and defined the “good life”, ethicists debated the shift in health-care decision-making for the concept of “sanctity of life” to “QoL” and social utility, environmentalists have placed emphasis upon attributes and conditions of the physical and biological environment, economists were concerned with the allocation of resources to achieve alternating goals, psychologists considered human needs and their fulfillment, where as sociologists have advanced a social systems approach in which indicators of QoL are seen as variables in the total system and its subsystems. Physicians focused on health- and illness-related variables and nurses, on keeping with the discipline’s holistic approach, took the broadest view in defining life quality, yet because of their frequent preoccupation with the physiological status, they tend to contaminate their operationalization of the concept with disease-specific items [2,3]. And within these disciplines, scientists have defined QoL from different perspectives, such considerations as objective indicators, subjective view, life goals, needs satisfaction, and components of life. WHO defines Quality of Life as individuals 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. It is a broad ranging concept affected in a complex way by the person\'s physical health, psychological state, level of independence, social relationships, personal beliefs and their relationship to salient features of their environment [4,5].
Although health is one of the important domains of overall quality of life, there are other domains as well—for instance, jobs, housing, schools, the neighborhood. Aspects of culture, values, and spirituality are also key aspects of overall quality of life that add to the complexity of its measurement [6,7]. Nevertheless, researchers have developed useful techniques that have helped to conceptualize and measure these multiple domains and how they relate to each other [8].
Health-related quality of life (HRQoL) was adapted from the more general and wide-ranging concept ‘quality of life’. The concept of HRQoL and its determinants have evolved since the 1980s to encompass those aspects of overall quality of life that can be clearly shown to affect health—either physical or mental [9]. Health-related quality of life is a multi-dimensional concept that includes domains related to physical, mental, emotional and social functioning. It goes beyond direct measures of population health, life expectancy and causes of death, and focuses on the impact health status has on quality of life [10,11].
In the field of medical research, medical sociologist and scientists were concerned with evaluating aspects of life that are affected by disease or treatment for disease, hence, the term health-related QoL were used and included as a criterion for determining the outcome of illness and treatment [12,13].
HRQoL refers to the physical, psychological and social domains of health that are unique to each individual [3].Each of these domains can be measured by the objective assessments of functioning or health status and the subjective perceptions of health. Other valued aspects of life exist that are not generally considered as “health,” including income, freedom, and the environment. It has been defined as follows: “HRQoL is defined as the value assigned to duration of life as modified by impairments, functional states, perceptions, and social opportunities that are influenced by disease, injury, treatment, or policy” [8]. Another definition is “HRQoL can be defined as the functional effect of an illness and its consequent therapy upon a patient, as perceived by a patient” [14]. Lehman, Rachuba and Postrado (1995) also suggested that "HRQoL is the optimum level of mental, physical, role, and social functioning, including relationships, and perceptions of health, fitness, life satisfaction, and well-being" [15]. And Bird et al. (2000) defined HRQoL as: "the degree to which valued aspects of a person’s life have been influenced, positively or negatively by health and/or health-related interventions such as medical care" [12].
Over the years, consensus has been established that HRQoL is a multidimensional concept. As such, HRQoL is generally divided into 3 domains: physical, social, and psychological (Guyattet al.1993, Testa MA & Simonson DC, 1996). In the physical domain, perception and observation of normal or disrupted corporal functioning, such as mobility, pain, and nausea, are evaluated. In the social domain, the performance of societal functions is studied; these include activities of daily living and responsibilities in and out of the home, such as those associated with family, friends, and colleagues. In the psychological domain, mental and emotional functioning—for example, patients’ concerns, distress, and mood—are examined [4,6].
Briefly, HRQoL refers to the subjective perception of the effect of a disease or its treatment on one’s health and overall QoL. It includes physical, psychological, and social dimensions of health as assessed by the patient. It is clearly influenced by the individual’s beliefs, life experiences, personality, and expectations [6]. Emphasizing the inherently subjective nature of HRQoL is important. The physical dimensions of health (eg, disabilities, impaired physical strength) can be assessed “objectively” through either healthcare personnel or different instruments. These measurements provide information about the patient’s “health status” or “functioning.” HRQoL, on the other hand, assesses how the presence of the disease’s physical symptoms, such as impairment of physical functioning and reduced stamina, affect one’s overall well being, life satisfaction, or QoL. This means that two individuals with either similar physical health or equal severity of the disease could have vastly different HRQoL. Evidence accumulated over the last 10–15 years has clearly demonstrated that HRQoL measurements correlate with “objective” measures of physical health and predict traditional “hard outcomes” (ie, hospitalization and mortality) [16]. They also add additional information to the assessment of the overall well being of patients with chronic medical conditions. Clinicians and public health officials have used HRQoL and well-being to measure the effects of chronic illness, treatments, and short- and long-term disabilities. While there are several existing measures of HRQoL and well-being, methodological development in this area is still ongoing.
Recently there has been growing recognition of health‐related quality of life as an important indicator of the quality of care for patients with various illnesses. Monitoring patient-reported outcomes (PROs) including self-reported mental and functional health of individuals with chronic disease states is important for assuring optimal disease management and patient satisfaction. The subjective or self-reported state of well being, as it relates to the health condition, also known as “health related quality of life”, is a core PRO measure in individuals with End stage renal disease (ESRD). QoL may also serve as a prognostic measure and predictor for such other outcomes as survival.
In order to understand the relationship among the disease, its treatment, and HRQoL, the concept of illness intrusiveness must be understood. Illness intrusiveness was introduced to represent illness-induced disruptions to lifestyles, activities, and interests that compromise QoL [17]. Conceptualized as a facet of the chronic disease experience common across conditions, illness intrusiveness is a fundamental determinant of HRQoL. The central hypothesis is that disease (ie, pain, fatigue, disability) and treatment factors (ie, time required for treatment, untoward side effects) indirectly influence subjective well being and HRQoL through their effects on illness intrusiveness. For example, depriving the individual of the gratifying consequences of psychologically meaningful activities could affect the patient’s HRQoL. Psychological and social factors act as moderator variables that influence both the magnitude of illness intrusiveness, which is occasioned by disease and treatment factors, and the degree to which illness intrusiveness compromises QoL [18].
Over the past few decades, quality of life research endpoints have emerged as valuable research tools in assessing the outcome of therapeutic intervention in chronic diseases [19]. End stage renal disease is one such chronic disease causing a high level of disability in different domains of the patients\' lives, leading to impaired QoL [20,21]. The availability of various renal replacement therapies (RRT) has reduced the severity of symptoms and resulted in longer survival of ESRD patients [22]. Hemodialysis therapy is time-intensive, expensive, and requires fluid and dietary restrictions. Long-term dialysis therapy itself often results in a loss of freedom, dependence on caregivers, disruption of marital, family, and social life, and reduced or loss of financial income [23]. Hemodialysis alters the life style of the patient and family and interferes with their lives. The major areas of life affected by ESRD and its treatment includes employment, eating habits, vacation activities, sense of security, self-esteem, social relationships, and the ability to enjoy life [24]. Due to these reasons, the physical, psychological, socioeconomic, and environmental aspects of life are negatively affected, leading to compromised QoL [25].
Survival of ESRD patients has been largely improved nowadays because of medical progress, advanced technology, and beter patient care. Accumulated data in the recent decade show that health-related quality of life markedly influences dialysis outcomes. Attention thus needs to be focused not only on how long but also on how well ESRD patients live [26]. Compared with the general population, ESRD patients treated with hemodialysis have significantly impaired HRQoL [27].
Evaluation of HRQoL in patients with chronic diseases is becoming very important. HRQoL assessment helps to plan the individual strategy of treatment, to determine the efficacy of medical intervention, and to evaluate the quality of medical care. In comparison with HRQoL of the general population, it provides the opportunity to evaluate the psychological burden of chronic disease, and the effect of specific treatment [28].Some studies have shown international differences in HRQoL of ESRD patients treated with hemodialysis [29, 30].
An increasing number of professionals feel that HRQoL assessment is essential to evaluating quality and effectiveness of ESRD patient care, comparing alternative treatments and RRT modalities, improving clinical outcomes, facilitating complex rehabilitation of ESRD patients, and enhancing patient satisfaction. Several authors have suggested that regular HRQoL monitoring become part of regular ESRD patient assessment and incorporated into the continuous quality assurance and quality improvement systems [31,32].
ESRD is a life-threatening disease that leads to numerous and severe symptoms and complications. These severe comorbid conditions will have a major impact on the affected patients’ HRQoL. RRTs are able to alleviate, but they are very intrusive and cure neither the disease nor its symptoms. Patients suffering from ESRD need RRTs to survive, but they also expect to achieve a certain level of well being. In industrialized countries achieving survival is not enough for a treatment to be considered “successful” unless it also yields an appreciable gain in HRQoL [33,34]. Thus, the results of studies suggest that the QoL of hemodialysis patients is considerably impaired compared to that of the healthy subjects, especially with respect to the physical, psychological and social relationship domains [35,36]. In a previous DOPPS study, lower scores in several measures of HRQoL, particularly PCS, were found to be strongly associated with higher risk of death in Japan, Europe, and the United States [16]. Other studies have shown that patients on hemodialysis have a poor health-related quality of life (HRQoL) and present with complications such as depression, malnutrition, and inflammation. Many of them suffer from impaired cognitive functioning such as memory loss and abnormally low concentration, as well as other unhealthy physical, mental, and social aspects of life that can, and do, affect even the simplest activities of daily life [37,38]. On the other hand, many researchers emphasize that an improvement in HRQoL reduces the complications associated with this disease, or at least makes them more tolerable [39]. Therefore, it is useful to determine the level of renal function related to the decreasing point of HRQoL for the adequate intervention to enhance HRQoL in time. Improving QoL and other PROs in the dialysis patient population has evolved as a goal for renal replacement therapy.
End-stage renal disease patients undergoing hemodialysis (HD) has a considerable impact on the functional status and health-related QoL perceived by the patient as it is accompanied by symptoms that affect daily life [40].Over the years, several studies have assessed HRQoL in different ESRD populations. These reports reveal numerous sociodemographic, clinical, and psychosocial factors that are associated with impaired HRQoL.
Sociodemographic factors: It has been repeatedly demonstrated patients undergoing hemodialysis that female patients consistently report worse HRQoL than men [40,41]. Women had lower QoL scores than men, as already reported by the studies [42,43]; this may be explained by women\'s multiple domestic tasks and responsibilities that, unlike men, they cannot circumvent [44]. Also, one potential explanation may be the more negative disease perception and the increased prevalence of depression in women. Moreno et al.,(1996) in their multicenter cross-sectional study [36], and Sesso et al., (2003) in their prospective cohort study, also found that higher socioeconomic level was significantly related to better QoL [45]. A lower social status, characterized by lower education, worse financial situation, or lack of employment, has also been consistently associated with impaired QoL [41,46]. This association is important, as vocational and educational rehabilitation could substantially improve HRQoL. The association of age with HRQoL is quite complex and illustrates the complexity of the QoLconcept.Some studies conducted in different countries also demonstrated that age was strongly inversely associated with the physical domain scores [25].As age increases in the elderly, physical function of the body decreases [46-48]. The subjective QoL for elderly patients, however, varies depending on their expectations and beliefs. It could be surprisingly good compared to their younger counterparts [49].
Clinical factors: Several clinical factors are strongly associated with HRQoL in hemodialysis patients. The underlying kidney disease leading to renal failure, the presence and severity of diabetes [50,51] and comorbid conditions in general [49,52] and congestive heart failure in particular predict impaired QoL [53]. Anemia is highly prevalent in patients undergoing HD and is associated with adverse clinical outcomes and diminished HRQoL [54-59]. The most prominent symptoms of anemia are fatigue, dyspnea, and diminished sense of well-being. Less common symptoms include difficulty concentrating, dizziness, sleep disorders, cold intolerance, and headaches [60]. Walters et al. (2002) assessed health-related QoL, depressive symptoms, anemia, and malnutrition at hemodialysis initiation and found that 56% of the sample group (422) had a hemoglobin levels less than 10g/dl [38]. Chronic inflammation, presence of malnutrition, and different medications’ side effects have been reported to predict worse HRQoL [31]. However, it is important to note that the different comorbidity indices are used to measure comorbid burdens, and clinical and sociodemographic factors only explains a fraction of HRQoL variability.
Duration of dialysis plays an important role affecting QoL in dialysis patients. According to Vasilieva (2006), in linear regression analysis, duration of dialysis was a significant independent predictors of the low physical component score (PCS) in hemodialysis patients [61]. A similar observation was made by Anees et al. (2011); duration of dialysis had a reverse correlation with QoL. As duration of dialysis increases, QoL of dialysis patients deteriorates [62]. In another study, QoL was better in hemodialysis patients with a duration less than 8 months than patients with a dialysis duration more than 8 months [63].
Psychological/psychosocial factors: Several psychosocial factors have also been shown to strongly predict HRQoL scores. The expanding awareness about objective parameters and their impact on HRQoL is complemented by few studies on subjective symptoms and their influence on HRQoL in CKD [64-66]. The symptom burden that these patients struggle with include, fatigue [59,64,65], cognitive difficulties [59,64], sleep disturbances [34,59,64,67], sexual dysfunction [59,64], pain and depression [59,64,65], most of which are interlinked [65,67. While larger studies on pre-dialysis ESRD patients are lacking, existing ones confirm the negative impact of these symptoms on HRQoL [34,59,66].
In relation to psychological status, the a study by Mollaoglu (2004) indicated that two third of ESRD patients in Turkey had depression and found an association between depressed mood and health-related QoL [63]. The higher depression scores the lower health-related QoL scores. She explained that as a direct influence of chronic renal insufficiency on health-related QoL. Another study indicated that the mental health was significantly higher for patients treated in the United States than in Europe [68]. In another study by Jofre, Lopez-Gomez &Valderrabano (2000) who reviewed the factors affecting the QoL of renal failure patients, they found that the prevalence of depression is within 70% in the dialysis population using Beck Depression Inventory (BDI), they also indicated that depression has a significant impact on the perception of QoL [40]. Anxiety is another psychological response to hemodialysis patients and is related to the awareness of one\'s illness and the sense of dependency on the machine. Patients are concerned about the unpredictability of the illness and the disruption of their lives, they are chronically ill and fear dying [24].
Body image is also affected by dialysis treatment, making patients feel different, unattractive, and ill at ease within their own bodies. Access surgery often results in multiple scarring, involving the arms and chest. A fistula which is regarded as "very good" by dialysis staff can be seen as a horrible disfigurement by the patient, who may try to conceal it from friends and the curious stares of strangers. Many feel embarrassed in front of their partners and feel that nobody could find them attractive anymore [63,64].
Anxiety, loss of control, body image and sexual problems, social support, and unemployment are all factors that strongly influence QoL in hemodialysis patients. The utmost significance of these factors is further underlined by the fact that many of them are modifiable. Unfortunately, little attention is given to assess the potentially modifiable psychosocial stressors in hemodialysis patients.
Sleep disorders are highly prevalent in patients with renal impairment. The most frequent sleep disorders, such as restless legs syndrome, periodic leg movements in sleep, insomnia, and obstructive sleep apnea, are associated with significantly impaired HRQoL in patients with moderate renal failure not yet requiring RRTs as well as in patients on hemodialysis [17,32]
Health-related QoL assessment, as a supplement to more objective clinical indicators, is becoming more topical in view of the increasing questioning of the effectiveness and appropriateness of many existing medical treatments and methods of organizing health services [2,4]. The US Centers for Disease Control and Prevention CDC (1993) suggested that: measuring health-related QoL can help determine the burden of preventable diseases, injuries, and disabilities, and it can provide valuable new insights into the relationships between health-related QoL and risk factors. Measuring health-related QoL will help monitor progress in achieving the notions\' health objectives. Analysis of health-related QoL surveillance data can identify subgroups with relatively poor perceived health and help to guide interventions to improve their situations and avert more serious consequences [69].
In the field of nephrology, the evaluation of health-related QoL involves determining the efficiency and effectiveness of the different forms of renal replacement therapy (e.g. HD and peritoneal dialysis), evaluating the efficiency and effectiveness of the different types of other treatments applied to patients with ESRD (e.g., recombinant human erythropoietin therapy) and follow-up of the evolution of individual renal patients [43].
Different generic disease-specific instruments and domain-specific instruments have been used for assessing the QoL in patients undergoing hemodialysis (Germin-Petrovic et al. 2011).
Measures which implicitly or explicitly aim to tap health-related QoL. They encompass the dimensions of physical, mental and social health [69]. These instruments are intended for general use, irrespective for the illness or condition of the patient. These generic questionnaires may often be applicable to healthy people, too [13]. The Sickness Impact Profile, the Medical Outcome Study 36-Item Short Form, and the Nottingham Health Profile are examples of the generic instruments.
The SF-36 developed by Ware et al. in 1993 evaluates general health status, it is designed to provide assessments involving generic health concepts that are not specific to any age, disease or treatment groups. Emphasis is placed upon physical, social, and emotional functioning. It can be either self-assessed or administered by a trained interviewer. As the name implies, there are 36 questions addressing physical health and mental health [13].
The Nottingham Health Profile (NHP) was developed to be used in epidemiological studies of health and disease [70]. It consists of two parts. Part I contains 38 yes/no items in 6 dimensions: pain, physical mobility, emotional reactions, energy, social isolation and sleep. Part II contains 7 general yes/no questions concerning daily living problems. The two parts may be used independently. Part I is scored using weighted values which give a range of possible scores from zero (no problems at all) to 100 (presence of all problems within a dimension).
A 136-item self- or interviewer-administered, behaviorally-based, health status questionnaire. Everyday activities in 12 categories (sleep and rest, emotional behavior, body care and movement, home management, mobility, social interaction, ambulation, alertness behavior, communication, work, recreation and pastimes, and eating) are measured. Respondents endorse items that describe themselves and are related to their health. The SIP is scored according to the number and type of items endorsed. Scoring can be done at the level of categories and dimensions as well as at the total SIP level. It may be either interviewer- or self-administered [13].
The Quality of Life Index (QLI) was developed in the USA during the 1980s as a measure of morbidity for application in both normal and unwell populations [71]. The original instrument, with the addition of six dialysis-specific items, was developed and tested in patients receiving haemodialysis [71]; factor analysis confirmed instrument construction. The instrument comprises two sections assessing respondent satisfaction and relative importance of each domain, respectively. Each section has 32 items, with eight items per domain. Six-point ordinal response scales range from ‘very dissatisfied’ or ‘very unimportant’ (1), to ‘very satisfied’ or ‘very important’ (6). Scoring is complicated and the developers recommend a computer programme. In summary, importance scores are used to weight satisfaction scores; index or domain scores range from 0 to 30, where higher scores indicate better quality of life.
Regarding evidence in relation to kidney disease, reliability was supported for the QLI in a one month time interval for dialysis patients. High internal consistency was also reported in a small study by [71]and reproduced in a further study with a larger sample of patients [71]. Additional items for haemodialysis patients relating to treatment were added to each section (Satisfaction with various domains and Importance of the domain to the individual) in Ferrans and Powers 1985). Items were endorsed by patients receiving haemodialysis. A transplant version is also available which included two items relating to the potential for a successful transplant. This is for patients receiving haemodialysis and on the transplant list.
A four factor structure was supported in Ferrans and Powers (1985) of Health and functioning, socioeconomic, psychological/spiritual and family. A high order factor was revealed representing Quality of Life. Moderate correlation of QLI-D scores with a life satisfaction questionnaire has been reported [71]. Further convergent validity is supported for each domain and life satisfaction, with higher correlations for the Psychological/spiritual domain. Moderate correlation was reported between scores from the QLI-D and other patient-reported measures of symptoms and psychological adjustment to disease. Moderate correlation of scores has been reported between QLI-D and symptoms.
A larger population was recruited in another study by the developers [13]. This included 349 patients from a haemodialysis unit and questionnaires mailed to patients. 20% of patients had missing values greater than 15% and overall computable responses were available from 46% of participants invited. A 46% response rate was obtained to postal administration of the questionnaire [13].
The KDQOL-SF includes both general measures and measures specific to patients with kidney disease. The general measures were based on questions from the 36-item Short-Form Health Survey (SF-36), developed by Ware and Sherbourne [73]. Previous data support the use of the SF-36 and the KDQOL-SF as research instruments to HRQoL [74]. The internal consistency and reliability are similar among translations of the SF-36 and the KDQOL-SF [9,68]. Patient responses to the SF-36 questions were used to determine scores for the mental component summary (MCS) and the physical component summary (PCS). The scales for MCS and PCS are derived from eight different subscales: physical functioning role (physical, bodily pain, general health, and vitality) and social functioning role (emotional, and mental health).
The KDQOL-SF includes questions that supplement the SF-36. These additional questions were designed to assess the particular health-related concerns of individuals with kidney diseases and ESRD patients treated by dialysis [74]. The kidney disease component summary (KDCS) score, which corresponds to the MCS and PCS of the SF-36, is derived from 11 subscales: symptoms/problems, effects of kidney disease on daily life, burden of kidney disease, work status, cognitive function, quality of social interaction, sexual function, sleep, social support, dialysis staff encouragement, and patient satisfaction.
The SF-36 and kidney disease–targeted portions of the questionnaire were scored according to the manual by Ware et al (1993) and the KDQOL scoring manual (Hays et al.1994) [74]. On all scales, the possible scores range from 0 to 100; higher scores indicate more or better functioning, or better quality of life. The summary scales have the same interpretation, but do not span the entire 0 to 100 range.
This 26 itemed questionnaire was developed in Canada with the involvement of patients receiving haemodialysis and empirically by factor analysis. Five domains included are: Physical symptoms (6 individualised symptoms identified by the patient); Fatigue: 6); Depression (5); Relationships (6); Frustration (3). Responses are scored in a 7 point Likert scale during the last 2 weeks. It is reported to take 10 to 15 minutes to complete.
Reproducibility is supported with ICCs above 0.80 for all domains. Construct validity is reported with moderate correlations with analogous domains using the SIP. Trial data [76], provide support for responsiveness with significant improvement in scores for patients receiving treatment for anaemia which was consistent with score changes on the SIP.
The Renal Quality of Life profile (RQLP) is a 43 itemed questionnaire with a 5 point Likert scale for responses. Five dimensions include: Eating and drinking, Physical activities, Leisure time, Psychosocial activities and Impact of treatment. It was developed adopting a comprehensive methodology involving patients and clinicians in the UK [77].
Principal component factor analysis supported the five dimensions. A high response rate is reported in Barton et al., [78].The RQLP scores were responsive to change in a trial of pharmacy care compared to standard care for patients receiving HD. Effect sizes were moderate [78]. Moderate correlation is reported between the RQLP and SF-36 dimensions which were similar in construct.
The Choices for Healthy Outcomes in Caring for ESRD (CHOICE) study was designed to evaluate the effectiveness of alternative dialysis prescription. As part of the CHOICE study, the CHEQ as patient-reported HRQoL instrument was developed to specifically complement the SF-36; be sensitive to dialysis treatment modalities and regimes; and be useful for longitudinal evaluation. A comprehensive, patientcentred approach was used during development. Items were derived from interviews with patients; literature; and clinicians’ expertise [79]. The questionnaire has 83 items addressing 21 domains: the 8 domains of the SF-36, 8 additional generic domains (cognitive functioning, sexual functioning, sleep, work, recreation, travel, finances, and general quality of life); and 5 ESRD-specific domains (diet, freedom, body image, dialysis access. The original study byWu and colleagues (2001) provided some evidence for the reliability and validity of the scales. Adequate internal consistency is reported for most domains in Wu et al. (2001) [79].
This instrument was developed out of an instrument used in relation to diabetes, the Audit of Diabetes Dependent Quality of Life (ADDQoL) diabetes-specific individualized quality of life questionnaire. From a small study with patients in eight U.K. renal clinics each of the 13 ADDQoL items were found relevant and important for renal patients. Additional items were also identified by patients including physical appearance, dependency, freedom, restrictions of fluid intake, and societal prejudice [80]. No psychometric data for the new instrument were reported. No further studies using the instrument were identified.
The BI was developed in 1965 (Barthel, 1965)and later modified by Granger and coworkers (1979) as a scoring technique that measures the patient’s performance in 10 activities of daily life [81,82]. The BI is considered a reliable disability scale for stroke patients. The items can be divided into a group that is related to self-care (feeding, grooming, bathing, dressing, bowel and bladder care, and toilet use) and a group related to mobility (ambulation, transfers, and stair climbing). The maximal score is 100 if 5-point increments are used, indicating that the patient is fully independent in physical functioning. The lowest score is 0, representing a totally dependent bedridden state. The MRS measures independence rather than performance of specific tasks The BI examines the ability to perform normal or expected activities [13]. In this way, mental as well as physical adaptations to the neurological deficits are incorporated. The scale consists of 6 grades, from 0 to 5, with 0 corresponding to no symptoms and 5 corresponding to severe disability.
The McGill Pain Questionnaire, also known as McGill pain index, is a scale of rating pain developed at McGill University by Melzack and Torgerson [83].
To use the questionnaire, circle the words that describe your pain but do not circle more than one word in a group. Then when you have that done, go back and circle the three words in groups 1-10 that most convey your pain response. Pick the two words in groups 11-15 that do the same thing. Then pick one word in group 16. Finally, pick 1 word in groups 17-20. At the end you should have seven words that you can take to your doctor that will help describe both the quality of your pain and the intensity of it [13].
There is growing recognition of health-related QoL issues in ESRD patients undergoing hemodialysis. Considerable progress has been made in the treatment and health intervention of chronic kidney disease, however, health-related QoL continues to be a significant problem for patients receiving hemodialysis [31,39]. Hemodialysis patients are subjected to multiple physiological and psychological stressors and may be threatened with many potential losses and life style changes as they experience problems with disease-specific symptoms. The combination of a decrease in energy, the unavoidable emergence of socioeconomic problems, and emotional reactions compounds the stress facing the patient [38, 45]. The initiation of long-term dialysis treatment increases survival, but health-related QoL remains impaired. Therefore, researchers and clinicians generally agree that health-related QoL, its determinants and treatment options that may preserve subjective well-being merit continued investigation [62,63].
Health care workers should understand the health-related QoL of patients undergoing hemodialysis. The rich information collected can help health professionals to determine which patients may be at risk for diminished health-related QoL. It has direct consequences for clinical decision-making, rehabilitation and management of individual patients [65,72]. Draper (1992) stated that health professionals, in their decisions and actions, can influence their patient\'s QoL [84]. Additionally, they will be interested in promoting these conditions, which enhance life’s quality, and eliminating those that impair it. Health professionals working in hemodialysis units can direct resources to areas where improvement may be required. Patients can then have a greater chance of leading a fulfilling life. All these factors can positively influence the health-related QoL of patients, and directly benefit the family as well [62,63, 65]. This could be accomplished through health education and promotion of awareness about the disease, treatment options, complications and self-care activities. Counseling, on the other hand, is an important intervention that health professionals - with appropriate training - can provide. Referral of patients to the appropriate person according to their needs could be provided by an ordinary health professional who cares for the patient. Finally, health professionals can develop and implement rehabilitation programs for ESRD patients undergoing hemodialysis to assist them lead a productive life.
ESRD has a profound effect on HRQoL with the most prominent areas of difficulty being the physical domains. Hemodynamic instability is a major problem observed in hemodialysis patients and thus managed carefully. Anemia management in ESRD patients is a challenge for the health care team. The use of erythropoietin-stimulating agents (ESAs) has become a routine practice in hemodialysis patients in an effort to correct anemiaand improve HRQoL. Nonetheless, two simultaneously published trials [85,86] raised concerns regarding the optimal hemoglobin target levels. Druekeet al. (2006), the CREATE investigators, reported significant increment in HRQoL with higher hemoglobin levels whereas Singh et al. (2006), the CHOIR investigators, reported no difference in the HRQoL between the low and high hemoglobin arms after EPO therapy [86]. Additionally, normalization of hematocrit was shown to be associated with adverse cardiovascular outcomes in the CHOIR trial (2006). In consideration of the conflicting results of these publications, the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) published revised guidelines for the management of anemia in CKD patients [87], which were further reviewed at the Kidney Disease: Improving Global Outcomes (KDIGO) international conference. Members voiced a general consensus on maintaining target hemoglobin levels in the range of 11.0 to 12.0 g/dL (KDOQI 2007) and acknowledged the potential for harm associated with levels higher than 13.0 g/dL [87].
Considering the dramatically increasing prevalence of ESRD, the risk of progression of ESRD with hypertension and the significant impact of the disease on HRQoL, improving HRQoL is emerging as one of the therapeutic goals in hypertensive individuals. High blood pressure is managed by an appropriate choice of antihypertensive medications to have a target blood pressure of 125/75 mmHg. Cardiovascular risk factors are minimized as ESRD patients are at increased risk for coronary heart disease over the standard risk factors, prevention includes frequent monitoring of plasma lipid levels, diet control, and pharmacologic treatment of specific hyperlipidemias [87].
The increasing prevalence of ESRD in the older population and the poor prognosis and impaired HRQoL associated with frailty warrant early identification of high-risk patients. Suggested management strategies to prevent further deterioration include exercise training and correction of malnutrition, anemia, depression and hormonal imbalances. Growth hormone supplementation in elderly dialysis patients has been shown to improve muscle performance and HRQoL [88], but whether this approach would be helpful in patients with non-dialysis dependent CKD remains to be established.
Among the psychological stressors of ESRD patients undergoing HD, depression and anxiety are the most common problems encountered. The onset of ESRD and HD impacts significantly one\'s functional state and health-related QoL, it causes major alterations in the lifestyle of most patients, who may encounter frustration in all areas of life, this frustration causes depression which is known to be strongly associated to decreased health-related QoL. This is illustrated in Walters et al. (2002) study that assessed health-related QoL, depressive symptoms, anemia and malnutrition at HD initiation and found that HD patients who screened positive for depression (45% of the sample) scored lower on health-related QoL scale [38]. Anxiety, on the other hand, is detected in HD patients, and is caused by unstable health status leading to fears from worsening health condition, disturbed social relations, unemployment and consequent economic alterations, and even death. A study by White and Grenyer (1999) that aimed at investigating the impact of dialysis on both the patient and their partner found that dialysis patients had anxiety as they expressed uncertainty related to health instability within a progressively debilitating disease state and frequent interruptions of acute illness episodes [89].
Socioeconomic status is also altered in ESRD patients undergoing HD as chronic dialysis imposes a considerable burden on patients and families [17,38],the relationships of the patients with family members is altered as there is role reversal, with the assumption of added responsibilities by the spouse, resulting in a loss of authority for the patients [63]. Social isolation and decreased social interactions is observed in HD patients and this is caused by their health status and the treatment schedules. Another alteration of lifestyle includes the probable loss of financial security resulting from lower productivity and income, and possible unemployment. All the above factors are strongly related to health-related QoL of HD patients. Parkerson and Gutman, (2000) assessed health-related QoL of 103 ESRD patients on HD, and found that patients living with family reported more social support and better health-related QoL, general health, emotional well-being, social health and quality of social interactions than other patients [89].
The development and evaluation of effective interventions to reduce psychological distress, improve QoL and enhance social intimacy are of clinical and scientific importance to HD patients, their family members and healthcare providers. Tsayand Lee, (2005) randomized patients with end-stage renal disease to a cognitive–behavioural coping skills and stress management training programme or standard care (primarily education) [91]. Cognitive–behavioural treatment reduced symptoms of stress and depression, and improved QoL, compared with a standard care condition. Chang et al. (2004) combined education, vocational rehabilitation and social support enhancement, and found significant QoL improvements in ESRD patients [92]. Gross et al. (2004) used a mindfulness-based stress reduction programme in ESRD patients to reduce depression and anxiety, although no QoL improvements were found. Quality of life therapy (QoLT) is the only cognitive–behavioural treatment that targets happiness and life satisfaction in multiple life domains (e.g. relationships, enjoyable activities, self-esteem, etc.) with a specific goal of improving overall QoL [93]. This is important because the World Health Organization has emphasized the importance of a patient’s subjective perception of life in the context of his or her value systems, goals, expectations and standards.
Although advances in dialysis treatment have contributed to improved survival of patients with end-stage renal disease,such individuals particularly those treated by hemodialysis, health-related quality of life is much lower for those patients than for the general population. Impaired health-related QoL, dependence on others, and poor rehabilitation all contribute to physical and emotional disabilities that may persist even in well-dialyzed ESRD patients. Chronic HD patients are subjected to multiple physiological and psychological stressors and may be threatened by many potential losses and lifestyle changes. Analysis of health-related QoL surveillance data can identify subgroups with relatively poor perceived health and help to guide interventions to improve their situations and avert more serious consequences. Developments of HD technology, treatment of comorbidities, continuous patients\' education, social and psychological support may improve the HRQoL in these patients.
The skin is the largest organ of the human body with several vitally important functions. The skin acts as barrier against adverse effects of the surrounding environment on the organism, such as chemical factors, radiation factors, particularly ultraviolet light, and microbial infection. Other important functions of skin include thermoregulation, sensation of temperature, touch, pressure, and pain, keeping appropriate moisture in the underlying tissues, excretion of ions, water, and various biomolecules (e.g., lipids and proteins), and also production and storage of various biomolecules, such as pigments, vitamin D, and keratins for formation of epidermal appendages (for a review, see [1, 2]). Skin severely and chronically damaged by trauma, burns, bedsores, and by various diseases, e.g., diabetes, cannot exert these functions, which can lead to amputation and even death. Therefore, there is essential need to regenerate the damaged skin, particularly by methods of skin tissue engineering and induction of active wound healing. For these purposes, nanofibrous scaffolds seem to be one of the most promising materials. Nanomaterials in general are defined as features not exceeding 100 nm at least in one dimension, i.e., in diameter in case of nanofibers. However, nanofibers usually used in tissue engineering are often thicker (i.e., several hundreds of nm). In fact, they are submicron-scale fibers, but the term “nanofibers” has become widely used for them. Nanofibers can be obtained by various techniques, such as biological synthesis (e.g., nanocellulose produced by bacteria), self-assembly, phase separation, interfacial polymerization, suitable for electrically conductive materials, melt processing or antisolvent precipitation, and particularly by electrospinning, which has emerged as a relatively simple, elegant, scalable, and efficient technique for fabrication of polymeric nanofibers (for a review, see [2, 3, 4, 5]).
The advantage of nanofibrous scaffolds is that they mimic the fibrous component of the natural extracellular matrix (ECM), and therefore they can serve as ECM analogues for tissue engineering. In addition, nanofibrous meshes can act as a protective barrier against penetration of microbes into wounds, can keep the moisture in the damaged skin, and, at the same time, allow gas exchange and absorb the exudate from the wounds. These meshes can also be loaded with various bioactive molecules, such as growth and angiogenic factors, cytokines, hormones, vitamins, antioxidants, antimicrobial and antitumor agents, amino acids (
The nanofibrous scaffolds for skin tissue engineering and wound healing have been prepared from a wide range of synthetic and nature-derived polymers. Both these groups of polymers contain polymers relatively easily degradable in the human organism, and polymers which are non-degradable or slowly degradable. This review is focused on synthetic polymers, which have been used for creation of nanofibrous scaffolds for skin tissue engineering and wound healing applications. Typical and widely used degradable synthetic polymers include polylactides [9, 10] and their copolymers with polyglycolides [11], or polycaprolactone [6, 12] and its copolymers with polylactides [13]. Examples of biostable synthetic polymers are polyurethane [7], polydimethylsiloxane [14], polyethylene terephthalate [15] or polyethersulfone [16]. Polymers degradable in the human body are suitable as direct scaffolds for skin tissue engineering, while biostable polymers can be rather recommended as “intelligent” wound dressings delivering cells (keratinocytes, fibroblasts or stem cells) and bioactive molecules into wounds.
However, polymers in nanofibrous scaffolds are predominantly used in various combinations—synthetic with natural, degradable with non-degradable—and also in combination with various nanoparticles, e.g., mineral nanoparticles [17], carbon-based nanoparticles [1, 18] or metal-based nanoparticles [19, 20]. The reason of these combinations is to improve the stability, spinnability, wettability, mechanical properties, and bioactivity of nanofibers. The combination of various polymers, nanoparticles, and other components is a strategy commonly used to obtain hybrid materials possessing properties better than those of the individual constituents, regarding their use in scaffolds for tissue engineering or as material for wound dressing [21]. For example, synthetic polymers do not contain adhesion motifs recognizable by cell adhesion receptors, and combination with nature-derived polymers, which are proteins (collagen, gelatin, keratin, fibrin [6, 10, 22, 23]) or polysaccharides (hyaluronic acid, sulfated glycosaminoglycans, such as heparin [24, 25]) can endow them with these motifs, because these polymers are often components of ECM.
In electrospun nanofibrous meshes, the polymers can be combined by various approaches. In blending electrospinning, the polymers are mixed, filled in the same syringe, and electrospun together, which results in creation of fibers with two or more components randomly distributed within a fiber. In multi-jet electrospinning, each polymer is filled in a separate syringe and electrospun individually, which results in creation of meshes with two or more types of nanofibers. These types of nanofibers can be electrospun either concurrently and distributed randomly (i.e., mixing electrospinning) or alternatively and arranged into separate layers (i.e., multilayering electrospinning). In co-axial electrospinning, hybrid nanofibers with a core-shell architecture are created by spinning of two different solutions filled into outer and inner compartments of a co-axial syringe. Finally, an electrospun polymer can be secondarily coated with other polymers or bioactive substances [22, 26, 27, 28] (Figure 1).
Modes of combination of various polymers and compounds in nanofibrous scaffolds.
Nanofibrous meshes for skin tissue engineering can also be combined with other material types, such as porous 3D scaffolds or hydrogels in order to reconstruct two main skin layers, i.e., epidermis containing keratinocytes and dermis containing fibroblasts [23, 29, 30, 31]. Another advanced approach promising for construction of dermo-epidermal replacements is centrifugal jet spinning, capable of large-scale production of nanofibrous 3D scaffolds [32, 33].
In the waste majority of studies dealing with skin tissue engineering based on nanofibrous scaffolds, keratinocytes have been cultivated in a conventional static cell culture system, submerged into the culture media, although under physiological condition in vivo, keratinocytes are exposed to air. Therefore, in advanced skin tissue engineering, it is necessary to cultivate keratinocytes under appropriate mechanical loading, i.e., strain stress [34] or pressure stress [35], and simultaneously to cultivate them on the scaffolds exposed to the air-liquid interface [34, 36].
This chapter summarizes earlier and recent knowledge on skin tissue engineering and wound dressing applications, based on nanofibrous scaffolds made of synthetic non-degradable and degradable polymers, including our results.
Synthetic non-degradable polymers, explored for creation of electrospun nanofibrous meshes for skin regenerative therapies, included polyurethane, polydimethylsiloxane, polyethylene terephthalate, polyethersulfone, and even polystyrene. This group of polymers also includes non-degradable hydrogels, such as poly(acrylic acid), poly(methyl methacrylate), and poly(di(ethylene glycol) methyl ether methacrylate).
Polyurethane (PU) has been most frequently used from the mentioned polymers, which is due to its elasticity, and also possibility to prepare it in a degradable form, e.g., as poly(ester-urethane) urea (PEUU), which facilitates its applicability in skin tissue engineering [37], while the non-degradable forms of PU (and other non-degradable polymers in general) are rather used in wound dressing applications. Non-degradable PU nanofibrous meshes has been tested as advanced wound dressings loaded with various healing, angiogenic, anti-inflammatory, antioxidant, and antimicrobial substances. For example, blending PU with propolis improved the mechanical strength and hydrophilicity of the nanofibrous membrane, its cytocompatibility with fibroblasts and its antibacterial activity [38]. Blending PU with virgin olive oil endowed the nanofibrous meshes with photoprotective and antioxidant properties [19]. Dextran in composite PU/dextran fibers had angiogenic activity, and also served as a carrier for incorporation of β-estradiol, which accelerated healing of acute cutaneous wounds by its potent anti-inflammatory activity [7]. Another promising nanofibrous membrane applicable for wound dressing was prepared from electrospun PU, treated by plasma and subsequent spraying with chitosan solution containing an inclusion complex of β-cyclodextrin encapsulating berberine, i.e., an isoquinoline alkaloid with antimicrobial and anti-inflammatory activity [39]. Other antimicrobial substances incorporated into PU-based nanofibers included silver nanoparticles [20, 40], copper oxide nanocrystals [19] and antibiotics, such as silver-sulfadiazine [41] and amoxicillin [37]. In general, all these scaffolds showed none or low toxicity towards human HaCaT keratinocytes [20] or fibroblasts [19, 40], and no adverse reactions when implanted into laboratory animals in vivo [37, 41]. In addition, copper oxide is known by its angiogenic activity [19]. Nanofibrous meshes created by electrospinning from blends of PU with various concentrations of hydroxypropyl cellulose were also tested for transdermal drug delivery using donepezil hydrochloride, i.e., a drug used for treatment of Alzheimer disease [42]. PU was a component of a novel bilayer wound dressing, consisting of a commercial PU membrane as an outer layer, and an electrospun gelatin/keratin nanofibrous mat as an inner layer. The outer layer acted as a barrier against bacteria and other contaminants, while the inner layers promoted the adhesion, spreading, migration and growth of fibroblasts in vitro, and vascularization and wound healing in rats in vivo [23].
Polydimethylsiloxane (PDMS) in electrospun nanofibrous scaffolds was used in blends with thermoplastic PU (TPU) in 90:10, 80:20, and 70:30 blend ratios of TPU and PDMS. The activity of mitochondrial enzymes and proliferation of human dermal fibroblasts significantly increased with the percentage of PDMS in the scaffolds [14].
Polyethylene terephthalate (PET) in combination with honey improved the morphology of chitosan-containing fibers, decreased the diameter of electrospun fibers, increased the fiber deposition area in the collector, and increased the water uptake capacities of the material, which is important for exudating wounds [15]. In another study, low-molecular weight cationic compounds were synthesized from re-purposed PET and used for self-assembling into high aspect ratio supramolecular nanofibers for encapsulation and delivery of piperacillin/tazobactam (PT), an anionic antibiotic. In a Pseudomonas aeruginosa-infected mouse skin wound model, the treatment with the PT-loaded nanofibers was more effective in comparison with free PT, as evidenced by significantly lower counts of P. aeruginosa at the wound sites, and by a histological analysis [43].
Polyethersulfone (PES) nanofibrous membranes, made by fine tuning of electrospinning parameters, supported the proliferation of fibroblasts similarly as standard tissue culture polystyrene, and when applied as experimental wound dressings in mice, they showed a higher exudate absorption capacity, higher epithelial regeneration, greater fibroblast maturation, improved collagen deposition, and faster edema resolution than control commercial wound dressings, namely Vaseline gauze dressing and a conventional gas permeable bandage [16].
Polystyrene (PS) in its amorphous state is a transparent and colorless material. It is a hard, stiff, and very brittle polymer with remarkable water vapor permeability, very high electrical resistance, and low dielectric loss. For wound dressing applications, PS was electrospun with poly(ɛ-caprolactone) and chamomile extract, containing phenolics and flavonoids, particularly apigenin with remarkable wound healing effect [44]. Electrospun polystyrene nanofibrous scaffolds were also applied for cultivation of skin cells in dynamic bioreactors and at the air/liquid interface [45, 46].
Poly(acrylic acid) (PAA) was recently used for preparation of nanofibers incorporated with reduced graphene oxide, intended for delivery of antibiotics, which was controlled by photothermal activation of the nanofibers [18]. In another study, electrospun nanofibers consisting of PAA and poly(1,8-octanediol-co-citric acid), i.e., a synthetic biodegradable elastomer, showed intrinsic antibacterial activity and were used for topical delivery of physiologically relevant concentrations of growth factors [47].
Poly(methyl methacrylate) (PMMA) nanofibers were used for construction of antiscarring wound dressings. PMMA containing polyethylene glycol and kynurenic acid, an antifibrotic agent, suppressed proliferation of fibroblasts in vitro, and when administered as wound dressing in rats in vivo, they inhibited expression of collagen and fibronectin, and enhanced the production of matrix metalloprotease 1 (MMP-1), an ECM-degrading enzyme [48]. In addition, core-shell nanofibers containing PVA and PMMA were used for delivery of ciprofloxacin hydrochloride, an antibiotic [49].
Poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA), a thermoresponsive polymer, was blended with poly(
Another thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAM) was used for fabrication of nanofibers for transdermal delivery of drugs, namely levothyroxine (T4), which helps to reduce deposits of adipose tissue [51].
Synthetic degradable polymers have been used as scaffolds for skin tissue engineering, but also as wound dressing releasing various bioactive molecules by a controllable manner. Degradable polymers typically used in these applications are aliphatic polyesters, such as poly-ɛ-caprolactone (PCL), polylactide (PLA), and poly(lactide-co-glycolide) (PLGA). These polymers were approved by the Food and Drug Administration of the United States of America (FDA) for many medical applications.
Poly-ɛ-caprolactone (PCL) has been used most frequently from the mentioned polymers. It is a semi-crystalline polymer with tunable mechanical properties, and has a good solubility in a variety of solvents, and hence it can be combined with variety of other polymers. In comparison to other polyesters, PCL is a slowly degrading polymer, which can be essential for specific applications [52], and products of its degradation are non-toxic in the nature [53]. The acidic products of polyester degradation can affect the healing processes after implantation and may lead to inflammation [54]. However, due to the slow degradation of PCL, this risk is significantly lower compared to PLA and PLGA, which degrade significantly faster [55]. Slower degradation of PCL in comparison with its copolymer with PLA (PLCL) was also confirmed in our study, where both polymers were exposed to enzymatic degradation using lipase and proteinase K enzymes [13] (Figure 2).
Scanning electron microscopy analyses of electrospun PCL (A, B) and PLCL (C, D) in their intact state (upper row, A, C) and after 2 days of enzymatic degradation (lower row, B, D). Magnification 5000×, scale bar 10 μm.
However, PCL is more hydrophobic than PLA and particularly PLGA, and thus it is less supportive for cell adhesion. Therefore, PCL was rarely electrospun alone, i.e., without other polymers and bioactive additives. Nevertheless, pure PCL nanofibrous scaffolds were successfully used for cultivation and differentiation of hair follicle stem cells, isolated from the bulge regions of rat whiskers [56, 57]. In addition, pure PCL scaffolds supported the proliferation of mesenchymal stem cells, fibroblasts, and keratinocytes better than pure PVA scaffolds [12]. In spite of this, for purposes of skin regenerative therapies, PCL was usually combined with natural polymers, such as collagen, which was either blended with PCL before electrospinning [6, 58], or deposited on PCL nanofibers [59]. Gelatin, a collagen-derived protein, was either blended with PCL [60], or incorporated into core-shell PCL/gelatin nanofibers as the core polymer [22]. Gelatin was also electrospun independently of PCL using a double-nozzle technique, which resulted in creation of two types of nanofibers in the scaffolds, either mixed [61] or arranged in separate gelatin and PCL layers [27]. Multilayered and blend structures were found to fit most of native skin requirements in comparison with all the other mentioned structures [27].
Other natural polymers for modification of PCL nanofibers included whey protein [62], hyaluronic acid [24], keratin [28, 63], chitosan [28], fibrinogen [64], or gum arabic, and a corn protein zein [65]. These natural polymers were blended with PCL in the electrospinning solution. Polymer-modified PCL nanofibrous scaffolds have been often further modified with growth factors, such as epidermal growth factor (EGF) immobilized on PCL/collagen nanofibers [58] or on PCL/gelatin nanofibers [60] and transforming growth factor-β1 (TGF-β1) added into PCL/collagen electrospinning solution [6].
Other bioactive substances used for incorporation into PCL-based nanofibers included medicinal herbs such as Aloe vera [61], lawsone, i.e., 2-hydroxy-1,4-naphthoquinone extracted from Henna, endowed with antimicrobial, antiparasitic, anticancer, and antioxidant activities [22], other plant extracts with wound healing effects, e.g., from Calendula officinalis [65] or Indigofera aspalathoides, Azadirachta indica, Memecylon edule, and Myristica andamanica [66], molybdenum oxide nanoparticles for treating skin cancer [67] or antibiotics, which can be combined with PCL by various manners, e.g., through whey protein [62] or through micelles coating PCL/collagen nanofibers [6].
In our experiments, PCL electrospun nanofibrous membranes were impregnated with alaptide or
Normal human dermal fibroblasts cultivated for 7 days on PCL nanofibrous membrane impregnated with alaptide or arginine. A—0.1 wt.% of alaptide, B—2.5 wt.% of alaptide, C—1 wt.% of arginine, 10 wt.% of arginine. The cells were stained for nuclei (blue) and actin (red) using DNA-binding dye DAPI and phalloidin conjugated with TRITC. The images were acquired using Olympus IX71 fluorescence microscope equipped with DP71 camera and lens 10× (N.A. = 0.3).
Polylactide (PLA) is a polymer obtained by the ring-opening polymerization of lactide, i.e., cyclic dimer of lactic acid, as the monomer. The lactide has two enantiomers, namely
For skin tissue engineering, similarly as in PCL, PLA was often combined with other polymers and biologically active molecules in order to tailor desirable properties of the scaffolds. For example, for enhancing the cell adhesion on nanofibrous PLA scaffolds, PLA was blended and electrospun together with gelatin. Composite scaffolds containing PLA and gelatin in a ratio of 7:3 were more suitable for the attachment and viability of fibroblasts than the scaffolds made either of PLA or of gelatin alone [9]. Similarly, composite nanofibrous scaffolds made by electrospinning of a blend of poly-
In another design of bilayer scaffolds for skin tissue engineering, PLLA in the form of microporous disc was combined with superficial chitosan/PCL nanofibrous mat. The disc was seeded with dermal fibroblasts, while the mat was used as substrate for keratinocytes. The porous structure of the scaffolds allowed humoral communication of both cell types, but the nanofibers prevented the direct intermingling of these cell types [29].
Other interesting application of PLA nanofibers was skin tissue engineering for the infected wound site. PLA solution was electrospun together with highly porous silver microparticles (AgMPs) or high surface area silver nanoparticles (AgNPs) and used as substrates for co-culture of human epidermal keratinocytes and Staphylococcus aureus. The scaffolds with AgMPs showed a higher and steadier release of silver ions and lower cytotoxicity towards keratinocytes than AgNPs-loaded scaffolds [75].
PLA nanofibers have also been widely used for wound dressing applications, where they were loaded with various bioactive molecules improving wound healing and preventing microbial infection. Examples include PLLA/zein nanofibrous mats loaded with Rana chensinensis skin peptides with antibacterial and antioxidative activity [76], electrospun PLLA nanofibrous membranes coated by an Aloe vera gel [77], nanofibrillar matrices prepared from blends of PCL and PDLLA loaded with ciprofloxacin [78] or composite electrospun membranes containing polylactide:poly(vinyl pyrrolidone)/polylactide:poly(ethylene glycol) (PLA:PVP/PLA:PEG) core/shell fibers, designed for treatment of burns and loaded with curcumin and HHC36 antimicrobial peptides [8].
In spite of all these encouraging results, PLA and PCL can elicit inflammatory response. Although inflammation is the first physiological stage of wound healing, followed by proliferation and remodeling, excessive inflammation can delay the wound healing and can lead to ulceration, fibrosis, scar formation or entering the wound into a chronic state [79, 80]. The inflammatory response to PLA and PCL was reduced in electrospun co-axial scaffolds containing nanofibers with bioactive gelatin shells and biodegradable synthetic cores of PLA and PCL [81]. Another approach was the incorporation of PLA scaffolds with anti-inflammatory drugs. PLA nanofibers with 20 wt.% of ibuprofen promoted the viability and proliferation of human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF) in vitro, reduced wound contraction in mice in vivo, and when seeded with HEK and HDF, also enhanced new blood vessel formation in wounds of nude mice [80]. In a study by Yaru et al. [82], PLA nanofibers were incorporated with salicylate, a signaling molecule in plants, but also exhibiting a wide spectrum of signaling activities in mammals, including antithrombotic, anti-inflammatory, antineoplastic, and antimicrobial actions [83]. In addition, electrospun nanofibrous PDLLA scaffolds were incorporated with microalga Spirulina, which has anti-inflammatory, antioxidant, antimicrobial, antiallergenic, anticancer, and antidiabetic effects. The scaffolds were seeded with mesenchymal stem cells derived from mouse kidneys and used for treatment of the third degree burns in mice [79].
PLA and PCL can be combined in a poly(
As mentioned above, blend nanofibers of P(LLA-CL) and PDEGMA were prepared for controlled drug and cell delivery [50]. P(LLA-CL) was also blended with gelatin [84], silk fibroin, vitamin E, and curcumin [85] or with silk fibroin, tetracycline, and ascorbic acid [86], which increased the proliferation of human dermal fibroblasts on these nanofibrous scaffolds and secretion of collagen by these cells. Co-axial nanofibers with P(LLA-CL)/gelatin shell and albumin core containing EGF, insulin, hydrocortisone, and retinoic acid supported proliferation and epidermal differentiation of ADSCs better than nanofibers prepared by a blend spinning of all mentioned components [26]. In combination with poloxamer (Pluronic) 123, P(LLA-CL) was also used for electrospinning of nanofibrous scaffolds for direct delivery of ADSCs into wounds in order to promote their healing [87].
In our experiments, composite PCL/PLCL nanofibers were coated either with platelet lysate, or with platelet lysate incorporated in fibrin assemblies [88] in various concentrations. Results for human keratinocytes (HaCaT cells) indicated that the presence of platelet lysate increased the metabolic activity and phenotypic maturation of keratinocytes. The best results were observed when the nanofibers were coated with fibrin together with platelet lysate (Figure 4).
Immunofluorescence staining of cytokeratin 10 (green), cytokeratin 14 (red), and nuclei (blue) of HaCaT cells after 7 days in culture grown on PCL/PLCL nanofibers. Cell on nanofibers without coating (A), coated with platelet lysate (B) and coated with fibrin assemblies with platelet lysate (C) are shown. Leica TCS SPE DM2500 confocal microscope.
Poly(lactide-co-glycolide) (PLGA) is a copolymer obtained by the ring-opening co-polymerization of two different monomers, i.e., lactic acid and glycolic acid. In skin regenerative therapies, it was applied for both skin tissue engineering and wound dressing. For these applications, PLGA was combined with various natural and synthetic polymers and bioactive compounds. For example, using bovine serum albumin as a carrier protein, vitamin C, vitamin D3, hydrocortisone, insulin, triiodothyronine, and EGF were simultaneously blend-spun into PLGA-collagen nanofibers. All these factors concertedly increased proliferation of fibroblasts and keratinocytes, while maintaining the keratinocyte basal state. In addition, vitamin C maintained its ability to facilitate secretion of type I collagen by fibroblasts, EGF stimulated proliferation of skin fibroblasts, and insulin potentiated adipogenic differentiation of fibroblasts [11]. In PLGA nanofibers, EGF was also combined with the local anesthetic lidocaine in order to accelerate wound healing in a rat model [89]. Coating PLGA nanofibers with a self-assembled complex of poly(ethylene argininyl aspartate diglyceride) polycation, heparin, and cargo growth factors, i.e., vascular endothelial growth factor (VEGF) and/or transforming growth factor-beta3 (TGF-β3), enhanced proliferation of human dermal fibroblasts and formation of tubular structures from human umbilical vein endothelial cells in vitro. In addition, these nanofibers reduced necrosis, improved vascularization, and maintained well-composed skin appendages in a mouse skin flap model in vivo [25]. Growth factors, namely recombinant human EGF and recombinant human basic fibroblast growth factor (bFGF), were also encapsulated in PLGA microspheres and loaded into hybrid scaffolds of PLGA and polyethylene oxide [90]. Both growth factors had a synergistic effect on the proliferation of human skin fibroblasts and increased the expression of genes for collagen and elastin in these cells [90]. Composite nanofibrous membranes containing PLGA and cellulose nanocrystals and loaded with neurotensin accelerated healing of full-thickness skin wounds in spontaneously diabetic mice [91]. Nanofibers created by electrospinning the dispersion composed of polyethyleneimine-carboxymethyl chitosan/pDNA-angiogenin nanoparticles, curcumin, PLGA, and cellulose nanocrystals showed antimicrobial and regenerative effects when transplanted into the infected full-thickness burn wounds in rats [92].
The PLGA nanofibers were also modified with ECM components. In a study by Shtrichman et al. [93], the PLGA nanofibrous scaffolds were modified with ECM deposited on these scaffolds by mesenchymal progenitor cells, derived from human embryonic stem cells, and human induced pluripotent stem cells, originating from hair follicle keratinocytes, which were cultured on the scaffolds and removed by subsequent decellularization. Subcutaneous implantation of the ECM-modified scaffolds in rats then showed that this stem cell-derived construct is biocompatible, biodegradable, and holds great potential for tissue regeneration applications. In addition, ECM-derived proteins, such as collagen and gelatin, can be electrospun directly together with PLGA [94]. In our earlier study, PLGA nanofibers were modified with fibrin or collagen in a similar manner as PLLA [10]. The morphology of these coatings, and also the behavior of HaCaT keratinocytes and human dermal fibroblasts on the coated and uncoated nanofibers, were similar on PLGA and PLLA [10].
PLGA-based nanofibrous meshes were also used for treatment of skin fibrosis and keloids, formed by abnormal proliferation of scar tissue at the site of cutaneous injury. Composite nanofibers of PLGA and poly(vinyl alcohol) loaded with kynurenine, a tryptophan metabolite, improved the dermal fibrosis in a rat model [95]. PLGA nanofibers releasing dexamethasone and green tea polyphenols significantly induced the degradation of collagen fibers in keloids on the back of nude mice [96].
Last but not least, PLGA nanofibers were also explored for transdermal delivery of drugs with poor oral absorption and limited bioavailability, e.g., Daidzein, a promising candidate for treating cardiovascular and cerebrovascular diseases [97], or for local delivery of anticancer drugs (for a review, see [98]).
Another important degradable polymer for fabrication of nanofibrous meshes for skin regenerative therapies is poly(ethylene glycol) (PEG), also known as poly(ethylene oxide) (PEO), depending on its molecular weight. PEG usually refers to polymers with a molecular mass below 20,000 g/mol, while PEO refers to polymers with a molecular mass above 20,000 g/mol.
In nanofibrous scaffolds, PEG or PEO have been usually used as auxiliary components improving electrospinnability, mechanical properties, and wettability of other polymers. For example, PEO was used to enable electrospinning of casein (i.e., a protein extensively used for drug delivery), which does not possess sufficient viscoelasticity due to its extensive intermolecular interactions [99], or to improve the electrospinnability and mechanical properties of silk fibroin [100]. As mentioned above, PEO or PEG was electrospun together with PMMA for creation of nanofibers delivering kynurenic acid [95] or with PLGA for delivery of human recombinant EGF and bFGF [90]. Other interesting applications of PEO include creation of electrospun carboxymethylcellulose/PEO nanofibers for delivery of viable commensal bacteria for preventive diabetic foot treatment [101], creation of three-dimensional scaffolds composed of PCL-PEG-PCL tri-block copolymer and iron oxide (Fe3O4) nanoparticles for skin tissue engineering [102], creation of biodegradable nanofiber mats based on thermoresponsive multiblock poly(ester urethane)s comprising PEG, poly(propylene glycol) (PPG), and PCL, which showed improved hydrolytic degradation compared to pure PCL and excellent adhesion of human dermal fibroblasts [103]. The adhesion and growth of fibroblast were also improved after combination of PLCL with Pluronic, i.e., a copolymer of PEO and poly(propylene oxide) (PPO) arranged in a tri-block PEO-PPO-PEO structure [104].
Other auxiliary polymers used for creation of nanofibrous scaffolds are poly(vinyl alcohol) (PVA) and poly(vinyl pyrrolidone) (PVP). In some studies, PVA is regarded as hydrolytically degradable [17, 105], while in other studies, it is considered non-degradable [106]. PVP has been reported to be hydrolytically degradable [105]. In addition, both PVA and PVP are hydrophilic and water soluble, and thus they can be removed from a composite polymeric mesh in water environment. This property of PVA, PVP, and also of PEG or PEO, can be used for creation of so-called “sacrificial fibers” in order to enlarge the pores in nanofibrous scaffolds for penetration of cells [107]; for a review, see [108, 109] or for tailoring the appropriate surface roughness of nanofibers inside the scaffolds. For example, PLLA was electrospun together with PVP in increasing concentrations, and after subsequent etching of PVP from the scaffolds in water environment, nano- and microfibers with increasing nanoscale surface roughness were obtained. Higher surface nanoroughness and porosity of PLLA fibers increased their hydrophilicity and their colonization with human dermal fibroblasts [32]. Other applications of PVA and PVP are similar to those of PEG or PEO, i.e., to increase spinnability of poorly spinnable substances used for skin regenerative therapies. For this purpose, PVA was combined with polysaccharides, such as gum tragacanth [110] or Schizophyllan [111], and PVP with Aloe vera [112]. Both PVA and PVP have been used to improve mechanical properties, wettability, and attractiveness for cell adhesion of various synthetic and natural polymers, particularly PCL [110] and chitosan [1]. PVA was used as emulsifier in fabrication of blended electrospun PLGA/chitosan nanofibers for potential skin reconstruction [113]. PVA and particularly PVP are important components of nanofibers delivering various biomolecules and drugs into skin, such as antibiotics (PVA [49], PVP [114]), kynurenine (PVA [48]), curcumin and HHC36 antimicrobial peptides (PVP [8]) or antimicrobial suberin fatty acids isolated from outer birch bark (PVP [115]). PVA and PVP were combined in electrospun nanofibrous membranes designed for sustained release of the antibiotic ciprofloxacin into wounds [116]. Nanofibers with cellulose acetate (CA) as the core material and PVP solution as the shell material were used for transdermal delivery of artemisinin, a potent antimalarial drug, which was incorporated into CA [117].
Tissue engineering in general, including skin tissue engineering, can be markedly improved by cultivation of cell-material constructs in dynamic bioreactors. These systems not only improve the supply of oxygen and nutrients to cells and waste removal, but also mechanically stimulate the cells with positive effects on their growth, differentiation, and phenotypic maturation.
First of all, the cell seeding can be improved in dynamic systems. In a study by Vitacolonna et al. [118], various methods of seeding fibroblasts on acellular dermal matrix were compared, namely static cell seeding after previous degassing of the matrix using a low-pressure syringe system, orbital shaker seeding, centrifugal seeding, and their combinations. Centrifugal seeding combined with matrix degassing significantly increased the seeding efficiency and homogeneity compared to the other methods.
Also the subsequent proliferation and other performance of cells can be markedly influenced by the dynamic cultivation. For example, human epidermal stem cells cultured on microcarriers in a rotary bioreactor exhibited higher proliferation and viability than the cells cultured in static conditions [119]. Human fibroblasts on nanofibrous poly(3-hydroxybutyrate-co-3- hydroxyvalerate) (PHBV) scaffolds, subjected to biaxial distension for periods of time in a dynamic bioreactor, developed elastin fibers, whereas the cells on the same scaffolds cultured under static conditions showed negligible elastin production [120]. Cyclic uniaxial stretching of human HaCaT keratinocytes on collagen-silicon sheets induced the production of metalloproteinase 9 (MMP-9), a proteolytic enzyme necessary for keratinocyte migration, in these cells [121]. Strain also improved the mechanical strength of an engineered skin containing electrospun collagen scaffolds, human dermal fibroblasts, and epidermal keratinocytes, which was probably a result of enhanced epidermal cell proliferation, differentiation, and increased ECM production [34]. The keratinocyte differentiation under mechanical tension can be attributed to up-regulation of h2-calponin, which associates with actin stress fibers and decreases the cell proliferation rate (for a review, see [122]). Another type of mechanical stimulation implicated in keratinocyte differentiation is pressure stress, which increases the concentration of intracellular calcium, a stimulator of keratinocyte differentiation [35, 123].
In our experiments, we have developed a custom perfusion dynamic culture system allowing cell cultivation on elastic silicone membranes and generating cyclic pressure stress. First, these membranes were treated with plasma in order to increase their wettability and their ability to attach thin films made of nanofibrillar cellulose [124]. Afterwards, the porcine adipose tissue-derived stem cells were seeded on this surface. After 7 days of mechanical stimulation, a multilayered cell structure was observed in dynamic conditions, whereas in static conditions, only a cell monolayer was formed (Figure 5).
Color-coded projection of porcine adipose tissue-derived stem cells cultivated on thin nanocellulose film structure in static (left) and dynamic conditions (middle). Fluorescence staining of nuclei (DAPI) and F-actin (Phalloidin). Right: Custom built culture chambers creating controlled mechanical stress and strain with perfusion. Below, formation of a multilayered structure of cells creating opaque layer on the nanocellulose-coated silicone membrane.
Increased concentration of calcium in keratinocytes and their differentiation can be also achieved by other means than mechanical stimulation, namely by stimulation with laser beam [125] or monodirectional pulsed electric current [126]. Electrical stimulation also enhanced the migration and proliferation of fibroblasts, expression of ECM proteins in these cells, and differentiation of these cells towards myofibroblasts, i.e., processes critical for wound healing [127]. The positive effect of electrical current on fibroblasts can be further combined with light stimulation of the fibroblast proliferation, e.g., on nanofibrous PCL scaffolds electrospun with a semiconductive polymer, namely poly(N,N-bis(2-octyldodecyl)-3,6-di(thiophen-2-yl)-2,5-dihydropyrrolo[3,4-c]pyrrole-1,4-dione-alt-thieno[3,2-b]thiophene) (PDBTT), subjected to the illumination from a red light-emitting diode [128]. Also magnetic stimulation can be effectively used in skin tissue engineering. For example, multilayered sheets of keratinocytes were obtained by cultivation of keratinocytes loaded with magnetite cationic liposomes in a magnetic field. After removal of the magnet, the sheets were released from the cultivation plates, and were harvested with a magnet. This technology was termed “magnetic force-based tissue engineering” [129].
In most experimental studies dealing with skin tissue engineering in vitro, keratinocytes are submerged in the cell culture media. However, in physiological skin in vivo, keratinocytes are exposed to air, at least their uppermost layer, i.e., stratum corneum, which is an impermeable barrier of cornified cell layers. Therefore, in advanced tissue engineering, keratinocytes should be exposed to the air-liquid interface (Figure 6) in order to achieve their phenotypic maturation and creation of the stratum corneum and the other epidermal layers, namely the basal, spinous, and granular layers [130].
The principle of cell cultivation in a conventional cell culture system (A) and at the air-liquid interface (B).
The early differentiation of human amnion epithelial cells towards keratinocytes, manifested by formation desmosomes, was more pronounced in cells cultured at the air-liquid interface than in cells submerged in the culture medium [131]. In another study, human ADSCs were transdifferentiated towards keratinocytes in a medium containing retinoic acid, hydrocortisone, ascorbic acid, and bone morphogenetic protein-4 (BMP-4). This medium enabled high expression of pan-cytokeratin in conventional 2D cultures, especially if the cells were grown on type IV collagen. When the cell cultures were lifted to air-liquid interface, significant stratification was observed, particularly on growth supports coated with type IV collagen or fibronectin, and epidermal differentiation markers, such as involucrin and cytokeratins 1 and 14, were induced [132].
At the air-liquid interface, the keratinocytes or cells differentiating towards keratinocytes have been cultured on various substrates, e.g., acellular dermis [133], porous sponge-like gelatin scaffolds incorporated with chrondroitin-6-sulfate and hyaluronic acid [134], de-epithelialized human amniotic membrane [135], collagen IV and fibronectin [132] and fibrin in the form of layer [131], hydrogel or clot [136]. On the mentioned substrates, keratinocytes were grown either alone or in combination with fibroblasts submerged in the culture medium. In a study by Wang et al. [134], fibroblasts were grown inside the porous gelatin-based scaffolds submerged in the medium, while keratinocytes were grown on the top of the scaffolds, exposed to the air-liquid interface. Similarly, on the de-epithelialized amniotic membrane, fibroblasts were cultured on the lower side of the membrane, submerged in the culture medium, while keratinocytes were grown on the upper side at the air-liquid interface [135]. In a study by Keck et al. [136], even a three-layered skin substitute was created. For the hypodermal layer, ADSCs and mature adipocytes were seeded within a fibrin hydrogel. On this layer, a fibrin clot with incorporated fibroblasts was placed for construction of the dermal layer. Keratinocytes were then added on the top of the two-layered construct and cultured at the air-liquid interface in order to create the epidermal layer [136].
Regarding the use of nanofibrous scaffolds for cultivation of keratinocytes at the air-liquid interface, synthetic and nature-derived scaffolds were used, namely electrospun PCL scaffolds [137, 138], electrospun polystyrene scaffolds [45] and fibrous sheets obtained after culturing human fibroblasts with ascorbic acid [139].
PCL scaffolds were used for construction of a three-dimensional in vitro skin model. The scaffolds were seeded with keratinocytes and melanocytes isolated from human scalp skin and cultured at the air-liquid interface. The keratinocytes contained a number of keratin fibrils and membrane-coated granules and formed a multilayered concentric structure, the surface of which became distinctly keratinized at the air-liquid interface. Cells with characteristic of melanocytes showed scattered distribution within the construct [137]. PCL scaffolds loaded with wound healing drugs, namely dexpanthenol and metyrapone, were used for a cell-based wound healing assay for rapid and predictive evaluation of wound therapeutics in vitro, using human HaCaT keratinocytes cultured at the air-liquid interface [138].
Interesting results were obtained on electrospun polystyrene scaffolds. In the absence of serum, keratinocytes, fibroblasts, and endothelial cells did not grow when cultured alone. However, when fibroblasts were cocultured with keratinocytes and endothelial cells, expansion of keratinocytes and endothelial cells occurred even in the absence of serum. Furthermore, the cells displayed native spatial three-dimensional organization when cultured at the air-liquid interface, even when all three cell types were introduced at random to the scaffolds [45].
The fibrous sheets produced by fibroblasts were used for creation of reconstructed human skin in vitro. After seeding the sheets with keratinocytes and the cell maturation in vitro, the reconstructed skin exhibited a well-developed human epidermis that expressed differentiation markers and basement membrane proteins [139].
The cultivation of keratinocytes at the air-liquid interface was also combined with cultivation of these cells in dynamic bioreactors, which further improved their growth and phenotypic maturation. Uniaxial strain stress (deformation of the cultivation substrate by 5–20%) further enhanced proliferation and epidermal differentiation of keratinocytes cultured at the air-liquid interface on electrospun collagen scaffolds containing fibroblasts in comparison with keratinocytes on unstrained cell-material constructs [34].
Also the perfusion with cell culture media showed beneficial effects on tissue-engineered skin constructs at the air-liquid interface. In a perfusion system with various growth supports for cells, such as acellular human dermis, Azowipes, electrospun polystyrene, and an electrospun composite of polystyrene and poly-
Nanofibrous scaffolds made of synthetic polymers have been widely investigated for their potential use in skin regenerative therapies. Non-degradable polymers used for preparation of nanofibrous scaffolds included polyurethane (which can also be prepared in degradable form), polydimethylsiloxane (PDMS), polyethylene terephthalate (PET), polyethersulfone (PES), and even polystyrene (PS). These scaffolds were mainly intended for wound dressing applications, and in case of PS, also for cultivation of skin cells in dynamic bioreactor and at the air/liquid interface. For creation of nanofibrous meshes, the non-degradable polymers have been often used in combinations with nature-derived polymers (dextran, chitosan, gelatin, and keratin), and loaded with various wound healing, angiogenic, antioxidant, anti-inflammatory, photoprotective, and antimicrobial substances. Non-degradable synthetic polymers also include hydrogels, such as poly(acrylic acid) (PAA), poly(methyl methacrylate) (PMMA) and particularly poly(di(ethylene glycol) methyl ether methacrylate) (PDEGMA), which is thermoresponsive and suitable for controlled drug delivery and cell delivery into wounds. Degradable synthetic polymers have been also applied in wound healing, but also as direct scaffolds for skin tissue engineering, i.e., as carriers for keratinocytes, fibroblasts, and stem cells. The most widely used degradable polymers for these applications include polycaprolactone (PCL) and its copolymers with polylactides (PLCL), and also polylactides (PLLA and PDLLA) and their copolymers with polyglycolides (PLGA). Similarly as non-degradable polymers, also degradable polymers are almost exclusively used in combination with nature-derived polymers (collagen, gelatin, keratin, fibrin, and glycosaminoglycans) in order to increase their attractiveness for cell colonization, and also with some synthetic polymers, such as poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO), poly (vinyl alcohol) (PVA), and poly(vinyl pyrrolidone) (PVP). These synthetic polymers act as auxiliary, i.e., improving electrospinnability, mechanical properties, and wettability of other polymers. Similarly as non-degradable polymers, also degradable polymers have been loaded with a wide range of growth and angiogenic factors and other biologically active substances. The cell performance on non-degradable and degradable nanofibrous scaffolds can be further markedly improved by cultivation in dynamic bioreactors and/or at air/liquid interface.
This review article was supported by the Grant Agency of the Czech Republic (grant No. 17-02448S) and the Ministry of Health of the Czech Republic (grant No. NV18-01-00332).
IntechOpen publishes different types of publications
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