",isbn:"978-1-83962-718-7",printIsbn:"978-1-83962-717-0",pdfIsbn:"978-1-83962-754-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"4df95c7f295de7f6003e635d9a309fe9",bookSignature:"Dr. Yajuan Zhu, Dr. Qinghong Luo and Dr. Yuguo Liu",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/8969.jpg",keywords:"Water Cycle, Water Use Strategy, Vegetation Dynamics, Plant Community, Precipitation, Carbon Emission, Soil Respiration, Autotrophic Respiration, Algae Crust, Wind, Temperature, Vegetation Stability",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"January 26th 2021",dateEndSecondStepPublish:"February 23rd 2021",dateEndThirdStepPublish:"April 24th 2021",dateEndFourthStepPublish:"July 13th 2021",dateEndFifthStepPublish:"September 11th 2021",remainingDaysToSecondStep:"2 months",secondStepPassed:!0,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Zhu holds a Ph.D. in Ecology and is currently an Associate Research Professor at the Chinese Academy of Forestry at the Institute of Desertification Studies, she has led a number of national projects while working there.",coeditorOneBiosketch:"Dr. Luo holds a Ph.D. in Physical Geography and is currently a Research Professor at the Institute of Afforestation and Sand Control, Xinjiang Academy of Forestry. She is a holder of several technological patents in her area of research.",coeditorTwoBiosketch:"Dr. Liu holds a Ph.D. in Ecology and is currently an Assistant Professor at the Institute of Desertification Studies, Chinese Academy of Forestry. He has published several international works that have been recognized.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"180427",title:"Dr.",name:"Yajuan",middleName:null,surname:"Zhu",slug:"yajuan-zhu",fullName:"Yajuan Zhu",profilePictureURL:"https://mts.intechopen.com/storage/users/180427/images/system/180427.jpg",biography:"Dr. Yajuan Zhu obtained her Bachelor's degree in Agriculture from Northwest Agriculture and Forestry University in 2002 and PhD in Ecology from Chinese Academy of Sciences in 2007. She was a postdoctoral fellow working on the topic of land desertification control in the Research Institute of Forestry, Chinese Academy of Forestry, followed by her appointment as an Assistant Professor at the Institute of Desertification Studies, Chinese Academy of Forestry and currently she is an Associate Research Professor at the same institute. She is a Master's supervisor with interests in plant ecology in deserts, biodiversity, stable isotope ecology, isohydrology and desertification control.",institutionString:"Chinese Academy of Forestry",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Chinese Academy of Forestry",institutionURL:null,country:{name:"China"}}}],coeditorOne:{id:"340564",title:"Dr.",name:"Qinghong",middleName:null,surname:"Luo",slug:"qinghong-luo",fullName:"Qinghong Luo",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000032N5e7QAC/Profile_Picture_1605773886590",biography:"Dr. Qinghong Luo holds a Master's degree from Life Science College, Shihezi University (2006) and PhD in Physical geography from Xinjiang Ecology and Geography Institute, Chinese Academy of Sciences (2018). She was initially an Assistant Research Professor at Institute of Afforestation and Sand Control, Xinjiang Academy of Forestry, after an Associate Research Professor and currently she is a Research Professor at the same institute. Her research interests include desert vegetation dynamics, plant-soil interaction and desertification control among others. 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1. Introduction
\n
Bacterial tick-borne diseases (BTBDs) affect the productivity of livestock animals in various regions of the world, leading to a significant adverse impact on the production of resource-poor farming communities. Hence, the livestock industry has become an integral part of world economy, and the large number of dairy cattle is being imported between continents in order to meet an increasing demand of meat and dairy products, it is essential to review current status of bovine BTBDs and to identify diagnosis and prevention in the knowledge of BTBDs and their prevention. Although there has been a recent increase in the number of studies of BTBDs in various geographical regions, information on their prevalence, distribution, tick vectors and control is limited.
\n
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2. Bacterial tick-borne diseases of livestock animals
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2.1. Q fever
\n
Q fever is a zoonosis associated with Coxiella burnetii that is an obligate intracellular parasite classified within the family Rickettsiaceae and which can be divided into six genomic groups based on restriction fragment length polymorphism. Unlike the other members of Rickettsiae, C. burnetii is quite resistant to environmental influences and is not dependent upon arthropod vectors for transmission. C. burnetii exhibits two antigenic phases: phase I and phase II (Figure 1). Phase I organisms are more infectious. The organism has worldwide distribution, although a large serological survey argues that it is not present in New Zealand [1].
\n
Figure 1.
Coxiella burnetii mobilization in macrophages [2].
\n
C. burnetii cycles in a wide variety of wildlife species and their ectoparasites. The infection also cycles in domestic animals. Rates of infection in farm animals vary considerably between locations, between countries and with time as there appears to be cycles of infection within regions [3].
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In cattle, prevalence figures range from 6 to 82% of cattle and 23 to 96% of herds seropositive depending upon location and country. Seropositivity rates in sheep and goats are similar but also vary according to year and region. There is little information on management or other factors that might influence this variation in prevalence but one study found a significantly higher prevalence in housed cattle compared to cattle at kept at pasture. The transmission of infection is spread by direct contact and inhalation. Infection of non-pregnant animals is clinically silent and is followed by latent infection until pregnancy when there is recrudescence with infection in the intestine, uterus, placenta and udder and excretion from these sites at parturition. The organism is present in high concentration in the placenta and foetal fluids, and subsequent vaginal fluids are also excreted in urine and are present in the faeces of sheep from 11 to 18 days post-partum [4, 5]. Infection can result in abortion, stillbirths or poorly viable lambs but commonly the neonates of infected, excreting, ewes are born clinically normal. Abortion usually does not occur at successive pregnancies but there can be recrudescence of infection and excretion at these pregnancies, especially the one immediately following [6].
\n
Goats also excrete the organism in vaginal discharges for up to 2 weeks, and it is present in goat milk for up to 52 days after kidding and also in faeces. Maximum shedding in cattle also occurs at parturition and for the following 2 weeks but cattle excretes the organism in the milk for at least several months and up to 2 years and infection is common in bulk tank milk [7–10].
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There is strain variation in the organism and differences in plasmid sequence types have been correlated with differences in the type of disease occurring in humans. The organism is highly infectious, and it is estimated that the infective dose for humans approximates one organism zoonotic implications in human infection is primarily by inhalation. Sources of infection include such diverse materials such as soil, air-borne dust, wool, bedding and other materials contaminated by urine, faeces or birth products of animals. The potential for human infection from these sources is substantial; for example, ovine manure used as a garden fertilizer has been incriminated as a source. Sheep have traditionally been incriminated as the major reservoir of infection for humans, but the trend for urban populations to locate in close proximity to large dairy herds suggests that cattle could become an increasingly significant reservoir [11–13].
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The organism is found in the milk of infected livestock. A significant proportion of seropositive cattle excrete the organism in milk and periods and duration of excretion are variable but may persist at least 2 years. Rates of seropositivity in humans vary markedly between surveys, but there is a higher rate of seropositivity in people (farm workers, veterinarians, livestock dealers, dairy plant and slaughter house workers, shearers, etc.) that are associated with domestic animals and their products and with farm environments [14, 15]. Several incidents of infection in humans have been linked to exposure to parturient sheep and goats [16].
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Infection of ruminants can occur at any age and is usually clinically unapparent. In the experimental disease in cattle, anorexia is the only consistent clinical finding. Abortion occurs during the latter part of the lambing period in the flock and in the latter period of pregnancy in individual ewes. The dam shows no signs of impending abortion. As with sheep, infection in goats can be accompanied by abortion, but abortion in cattle is rare although it is recorded. Correlations between herd level seroprevalence and herd fertility are equivocal. There are a number of serological tests available including complement fixation, microagglutination, enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence (IF). The IF assay is used as the sero-reference test for the serodiagnosis of Q fever. It can detect antibody to phase variants and can provide epidemiological information as phase I antibody is associated with recent and acute infections and phase II antibody with chronic infections [17].
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There are seldom gross lesions in aborted foetuses, but foci of necrosis and inflammation are occasionally seen in the liver, lung and kidney microscopically. The placenta from aborting animals is usually thickened and a purulent exudates or large, red-brown foci of necrosis are typically seen in the thickened intercotyledonary areas. Microscopically, large numbers of necrotic neutrophils are usually visible on the chorionic surface and swollen trophoblasts filled with the organisms can also be found in well-preserved specimens. Examination of placental impression smears stained with Gimenez, Koster\'s, or other appropriate techniques provides a means of rapid diagnosis. However, care must be taken to avoid confusing Coxiella-infected trophoblasts with cells containing Chlamydophila organisms. Coxiellosis can be confirmed fluorescent antibody staining of fresh tissue or immunohistochemical staining of formalin-fixed samples. In most laboratories, culture is not attempted due to the zoonotic potential of this agent. Polymerase chain reaction (PCR) is the most accurate tool for the diagnosis of infectious abortions. In a previous study, six (4.3%) samples were detected PCR positive out of 138 samples [18]. In another research, C. burnetii gene was detected in 34.66% of the samples taken from 200 cattle, 200 sheep and 200 goats in the Aegean region of Turkey [19]. In a multidisciplinary research made with veterinarians, farm workers and butchers, among 92 people, 32 (34.8%) and 9 (9.8%) people were positive and equivocal by ELISA and immunoglobulin G (IgG), respectively. The ELISA positive and equivocal sera were studied further by the immunofluorescence antibody (IFA) test, and seven (7.6%) cases were confirmed with immunoglobulin M (IgM), 39 (42.4%) cases were confirmed with IgG. There was no significant difference for Coxiellosis seropositivity among the profession groups (p > 0.05). Only four (4.3%) cases were confirmed with PCR positive [20].
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Aborting animals should be isolated for 3 weeks and aborted and placental contaminated material burnt. Ideally, manure should be composted for 6 months before application to fields. Feed areas should be increased to keep them free from contamination with faeces and urine. While Q fever has significant implications for human health, it is not significantly important enough to have generated national or regional control strategies based on control in the animal population [21–23].
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Milk and milk products should be pasteurized. Veterinarians dealing with herds that provide raw milk should ensure that these herds are seronegative for C. burnetii. Vaccine trials with killed vaccines in animals show a good and persistent antibody response and suggest that vaccination can limit the excretion of the organism. However, there is little economic incentive for a vaccination programme involving livestock, and livestock vaccines are not available in most countries [24].
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\n
2.2. Rickettsiosis
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The members of the family Rickettsiaceae have cell walls similar to those of other Gram-negative bacteria. Ultra structural studies have shown that the Anaplasmataceae family have outer membranes but lack an obvious peptidoglycan layer [25]. Organisms in the family Rickettsiaceae, referred to as rickettsiae, generally target endothelial cells. Although several new species of rickettsiae have recently been identified in domestic animals using molecular techniques, their pathogenicity is uncertain and currently the only species of veterinary importance in the family Rickettsiaceae is Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever. Many Rickettsia species including the causal agents of typhus (R. prowazekii), murine typhus (R. typhi) and scrub typhus (R. tsutsugamushi) are primarily human pathogens. These highly pathogenic organisms have a predilection for the endothelial cells of small blood vessels, resulting in vasculitis and thrombosis in many organs. Rickettsia species produce phospholipase that damages the membranes of phagosomes allowing the organisms to escape into the cytoplasm (Figure 2). R. rickettsii replicates in both the cytoplasm and the nucleus of host cells, inducing cytotoxic effects [26].
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Definitive classification of the members of the Rickettsiales is based on 16S ribosomal ribonucleic acid (RNA) sequencing, lipopolysaccharide content and metabolic requirements. In diagnostic laboratories, identification of these organisms is based on the species affected, cell predilection, microscopic appearance and molecular techniques. Some members of the Rickettsiales can be cultured in embryonated eggs or tissue culture cells. These difficult procedures are usually performed only in laboratories engaged in research or vaccine production [28].
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Figure 2.
Infection diagram of R. rickettsii [27].
\n\n
R. rickettsii affects mainly humans and dogs. Rhipicephalus sanguineus and Amblyomma cajennense are the main vectors in Central and South America. Ticks acquire the pathogen while feeding on infected small wild mammals [29].
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An infected tick must remain attached for up to 20 hours before salivary transmission to the host occurs. The organisms, which replicate in endothelial cells of infected dogs, produce vasculitis, increased vascular permeability and haemorrhage. Rocky Mountain spotted fever should be considered in dogs with systemic diseases, which have been exposed to ticks in endemic areas. Indirect fluorescent antibody test (FAT) or ELISA demonstrating an increasing antibody titre to R. rickettsii is diagnostic. Antibodies are not demonstrable until at least 10 days after infection. A marked thrombocytopenia and leucopoenia may be present during the acute phase of the disease. The disease must be differentiated from acute canine monocytic ehrlichiosis. PCR detection in tick tissues has been described by a number of workers. Tetracycline therapy, which usually produces clinical improvement within 24 hours, must be continued for 2 weeks. Supportive therapy is necessary for severely debilitated dogs. Frequent removal of ticks is recommended. Because the disease is zoonotic, gloves should be worn during this procedure or a forceps should be used [30].
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Ticks acquire the pathogen while feeding on infected small wild mammals. R. rickettsii is maintained in the tick population by transovarial and transstadial transmission and thus the tick acts as both a reservoir and a vector of the organism. An infected tick must remain attached for up to 20 hours before salivary transmission to the host occurs. The incubation period of the disease is 2–10 days and the course is usually less than 2 weeks. Clinical signs include fever, depression, conjunctivitis, retinal haemorrhages, muscle and joint pain, coughing, dyspnoea and oedema of the extremities [31].
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2.3. Borreliosis
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Borreliae, which are longer and wider than other spirochaetes, have a similar helical shape. In addition to a linear chromosome, which is unique among bacteria, borreliae possess linear and circular plasmids, some of which appear to be essential for growth and survival of the organism. Although these spirochaetes can cause disease in animals and humans, subclinical infections are also common. Borreliae are transmitted by arthropod vectors. Arthropod vectors are responsible for transmission of Borrelia species in animals. Borreliae are obligate parasites in a variety of vertebrate hosts. Although these organisms persist in the environment for short periods, they depend on vertebrate reservoir hosts and arthropod vectors for long-term survival. Associations of certain Borrelia species with particular arthropod vectors and reservoir hosts are important in determining the epidemiology of infections with Borrelia species. After entering the bloodstream of a susceptible host, borreliae multiply and are disseminated throughout the body (Figure 3). Organisms may be demonstrated in joints, brain, nerves, eyes and heart. Whether disease is caused by active infection or by host immune responses to the organism is unclear. Persistent infection leading to the induction of cytokines may contribute to the development of lesions [32]. There may be an association between different genotypes of Borrelia burgdorferi and particular clinical syndromes in humans; B. burgdorferi sensu stricto (s.s.) is frequently associated with arthritis, B. garinii with neurological disease and B. afzelii with skin disease [33, 34].
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Chickens have been infected experimentally, and it was found that these animals quickly became immune to B. burgdorferi s.s. and did not show any clinical symptoms [36]. More recent studies have shown that pheasants can function as reservoir hosts of B. garinii and B. valaisiana in the United Kingdom (UK) [37], but no symptoms of disease in infected birds have been reported.
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Figure 3.
Life cycle of Borrelia spp. [35].
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Most infections are subclinical. Serological surveys demonstrate that exposure is common in both animal and human populations in endemic areas. The clinical manifestations of Lyme disease are mainly related to the sites of localization of the organisms. Clinical disease is reported frequently in dogs. Symptoms include fever, lethargy, arthritis and evidence of cardiac, renal or neurological disturbance. In the United States of America (USA), arthritis is a common finding whereas neurological disturbance is the most frequent clinical feature in Europe and Japan. The clinical signs in horses are similar to those in dogs and include lameness, uveitis, nephritis, hepatitis and encephalitis. However, some authors observe that definitive evidence of clinical Lyme disease in horses is lacking [38]. Lameness in cattle and sheep associated with B. burgdorferi sensu lato infection has been reported.
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Laboratory confirmation of Lyme disease may prove difficult because the spirochetes may be present in low numbers in specimens from clinically affected animals. In addition, the organism is fastidious in its cultural requirements. A history of exposure to tick infestation in an endemic area in association with characteristic clinical signs may suggest Lyme disease. Increasing antibody titres to B. burgdorferi sensu lato along with typical clinical signs are indicative of disease. Because subclinical infections are common in endemic areas, high titres alone are not confirmatory. The ELISA is extensively used for antibody detection; western immunoblotting is sometimes used for confirmation of ELISA results. It has been shown that ELISA techniques based on this antigen may be able to differentiate naturally infected and vaccinated animals [39]. Immunofluorescence assays may also be used but the results of these methods may be difficult to interpret. Culture of borreliae from clinically affected animals is confirmatory. Cultures in Barbour-Stoenner-Kelly medium should be incubated for 6 weeks under microaerophilic conditions and should be carried out in specialized laboratories. Low numbers of borreliae can be detected in samples by PCR techniques.
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Acute Lyme disease responds to treatment with amoxicillin and oxytetracycline. In chronic disease, prolonged or repeated courses of treatment may be required. Acaricidal sprays, baths or dips should be used to control tick infestation. Where feasible, tick habitats such as rough brush and scrub should be cleared. Prompt removal of ticks from companion animals may prevent infection. However, because some tick species can transmit spirochetes shortly after attachment, it cannot be assumed that daily removal of ticks will prevent infection [40].
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A number of vaccines, including whole cell bacterins and recombinant subunit vaccines, are commercially available for use in some countries. An outer surface protein A (OspA) recombinant vaccine stimulates the production of antibodies, which are able to kill the borreliae in the gut of the tick and thus prevent infection of the host. However, the benefit of vaccinating animals with currently available vaccines is disputed [41].
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2.4. Ehrlichiosis and anaplasmosis
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Ehrlichia (Cowdria) ruminantium is a Gram negative, intracellular rickettsial organism in the genus Ehrlichia. It occurs in colonies or morulae with a predilection for the vascular endothelium and stains blue with Giemsa stain. The organism is coccoid, 0.2–0.5 μ in diameter. It can now be cultivated in vitro, and it can also grow in mice. Cyclical development is believed to take place in intestinal and salivary epithelia of ticks. Although strain differences exist, all isolates possess a major antigenic protein 1 (MAP 1) that is used for diagnosis. However, the antigen cross-reacts with other Ehrlichia spp., including Ehrlichia equi, the cause of equine granulocytic ehrlichiosis. Anaplasma spp. is obligate intraerythrocytic parasites belonging to the order Rickettsiales and infecting ruminants. Infection occurs more sporadically in temperate climate areas. In the USA and other countries, the disease has occurred beyond the boundaries of tick-infested areas and the area distribution in Europe has been advancing northward in recent years with sporadic cases in France, Switzerland, the Netherlands, Hungary and Austria. Anaplasmosis of sheep and goats has a distribution similar to that of cattle. Disease occurs sporadically in the northern states and Canada. In Australia, infection is closely related to the distribution of Boophilus microplus, which is restricted to the northern areas. Differences in enzootic and epizootic areas in South America and South Africa are also largely related to tick distribution and climate [42].
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Heartwater is limited in its occurrence to sub-Saharan Africa, Madagascar and three Caribbean islands of Guadeloupe, Marie Galante and Antigua. It is one of the main causes of death in imported breeds of cattle, sheep and goats in endemic areas. Heartwater has been diagnosed recently in the island of Mayotte in the Indian Ocean. Measures of disease occurrence in endemic areas, morbidity and mortality rates are low, but the percentage of sera positive titres for heartwater could be as high as 100% in adults, depending on the abundance of tick vectors [43]. Case mortality can be as high as 100% in peracute cases in sheep and goats and as low as 0–10% in cattle. The disease is less severe in indigenous breeds and related game animals reared in enzootic areas, some of which may become symptomless carriers. The N\'Dama breed in West Africa is said to be well adapted to heartwater, partly because it can resist tick burdens under the traditional farming system. The method of transmission in the Caribbean, cattle egrets are suspected to spread Amblyomma variegatum between islands. Consequently, heartwater is considered threats to the American mainland where potential vectors are present but do not harbour the disease or where the vector may be introduced and become established. Infection in ticks is transmitted transstadially and possibly transovarially. Vertical transmission to calves in colostral milk has also been reported. Several wild ruminants can be infected and become subclinical carriers and reservoirs. Ticks feeding on them can transmit the disease to domestic ruminants. The organism does not infect humans. Cattle are infected with Amblyomma marginale and Amblyomma centrale and sheep with Amblyomma avis. A. marginale will establish in sheep by experimental infection but A. avis will not infect cattle. A variety of species of wild ruminants in both North America and Africa can be infected and may have significance as reservoirs for A. marginale. In the United States, the black-tail deer in the West Coast region is believed a reservoir and a number of species of antelope play a similar role in South Africa. The prevalence of infection in cattle in endemic areas is very high with seropositivity rates exceeding 60% and often approaching 90%. Seropositivity is much lower in regions that interface between endemic and non-endemic regions. Source and methods of transmission recovery from acute infection result in persistent infection characterized by repetitive cycles of rickettsemia. Persistent carriers are the reservoir for herd infection. The level of parasitemia is often too low for detection by microscopy but can be detected by nucleic acid probe analysis. Transmission occurs biologically by ticks [44].
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Heartwater is the most important rickettsial infection of ruminants in Africa and it is regarded as the most important disease of ruminants. In general, heartwater is a more serious problem where Amblyomma habraeum is the vector. In countries or regions where there is endemic stability, losses from heartwater are minimal until new animals are introduced. On the other hand, since most losses are in exotic animals, heartwater is a major constraint to livestock improvement in sub-Saharan Africa. Furthermore, it has the potential to spread from the Caribbean to the American mainland. Heartwater requires the vector tick to get established in any community. Therefore, there is concern about possible illegal importation of infected animals or ticks to southern United States where potential vectors exist. In ewes intra-uterine infection appears to occur with ease in experimental cases provided the ewe is exposed during the latter two-thirds of pregnancy. In sheep and goats, infection is usually subclinical but in some cases, particularly in goats, a severe anaemia may occur and a clinical picture similar to that found in cattle may be seen. Severe reactions of this type in goats are most frequent when the animals are suffering from concurrent disease. Goats may show hyper excitability and may bite at inanimate objects. The experimental disease in lambs includes fever, constipation or diarrhoea, pale, icteric conjunctivae and severe anaemia 15–20 days after inoculation. The anaemia is not completely resolved in 3–4 months. A. avis are usually situated at the periphery of erythrocytes but as many as 40% of infested cells may show sub-marginal protozoa [45].
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The incubation period is 1–3 weeks after transmission in tick saliva. Depending on the susceptibility of individual animals and the virulence of the infecting organism, the resulting disease may be peracute, acute, subacute or mild and unapparent. Peracute cases show only high fever and death with terminal convulsions in 1–2 days. Acute cases are more common and have a course of about 6 days. A sudden febrile reaction is followed by inappetence and rapid breathing followed by the classical nervous syndrome that is characteristic of heartwater. It comprises ataxia, chewing movements. Profuse, fetid diarrhoea is frequent. Subacute cases are less severe but may terminate in death in 2 weeks or the animal may gradually recover. The mild form is often subclinical and is seen mainly in indigenous animals and wild ruminants with high natural or induced resistance. The case mortality rate in peracute cases is 100%, in acute cases 50–90% and in calves below 4 weeks of age it is 5–10%, most animals recover in mild cases [46].
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Haematological changes in heartwater are not specific but there may be thrombocytopenia, neutropenia, eosinopenia and lymphocytosis. Confirmatory diagnosis is based on identifying the Rickettsia in capillary endothelial cells using a Giemsa stained squash preparation of brain tissue at post-mortem. The rickettsiae occur as blue to reddish-purple colonies or morulae of five to several hundred coccoid organisms (0.2–0.5 μ in diameter) in the cytoplasm of the cells. An immunohistochemical staining technique has also been described [47]. Injection of blood into sheep may also be used as a diagnostic procedure. The available serological test is an indirect fluorescent antibody test used for surveys but the close antigenic relationship with other Ehrlichia spp. often leads to false positives. An ELISA based on recombinant MAP l protein of C. ruminantium was reported to be more sensitive. In general, clinical detection of heartwater is not always easy because all serological assays so far available have poor sensitivity or specificity. Diff-Quik staining of blood smears is as accurate as Giemsa in the detection of A. marginale and can be completed in 15 seconds as compared to nearly an hour for Giemsa. There are no diagnostic clinical chemistry findings. A rapid card agglutination test, which tests serum or plasma for antibodies against A. marginale, is cheap and quick, and sufficiently accurate to be used as a herd test. Currently, in most countries, the card agglutination and complement fixation (CF) tests are routinely available. It is also an accurate test for selecting recently affected animals. A dot-ELISA with high sensitivity, specificity and predictive value is also described and could be particularly applicable to field examinations. A competitive inhibition ELISA test, with high sensitivity and specificity, has been developed that detects antibody to a major surface protein that is conserved among Anaplasma species; this test can be used to detect cattle persistently infected for as long as 6 years. Vaccinated animals may react to all of the serological tests for periods of over 1 year. Nucleic probe analysis can be used to detect low levels of parasitaemia. Transmission to splenectomised animals has been used to detect carriers but is expensive and is now replaced by PCR in countries where this technology is available [48]. A polymerase chain reaction assay has therefore been suggested as the method of choice for detection of E. ruminantium infection [49].
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Field cases of heartwater are difficult to treat successfully because available drugs are effective only in early febrile stages before neurological signs develop. In the early stages, short-acting tetracyclines at 10–20 mg/kg body weight (BW) and long-acting forms at reduced doses are effective. Sulphonamides can also be used in the early stages but are less effective. Hyperimmune serum is said to be of no curative value. Supportive therapy to reduce either the pulmonary oedema or the neurologic signs or to stabilize membranes in general is being investigated but with little success. Chemoprophylaxis involves administration of tetracyclines or subcutaneous implantation of doxycycline in susceptible animals when they are introduced into an endemic area. Results are not always predictable. Anaplasmosis treatment is with tetracyclines. Treatment of clinical disease can be with oxytetracycline, 6–10 mg/kg BW daily for 3 days, or a one dose application of long-lasting 20 mg/kg oxytetracycline intramuscularly. The convalescent period is long. Concurrent administration of estradiol cypionate (14.3 mg/kg BW intramuscularly) appears to improve the rate of recovery by promoting parasitemia during treatment. Tetracycline treatment will not eliminate infection and immunity will persist. Blood transfusions are indicated in animals with a packed cell volume (PCV) less than 15%. Rough handling must be avoided. Imidocarb (3 mg/kg BW) is also an effective treatment for clinical cases and does not interfere with the development of acquired immunity to A. marginale. The risk for infection in the rest of the herd should be assessed and, if necessary, temporary or prolonged protection should be provided. Protection can be provided by tetracyclines, or by vaccination [50].
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Past efforts to control heartwater were based on intensive acaricide treatment in endemic areas. It involved frequent use of acaricides (plunge dipping) up to 52 times a year. This has now been shown to be environmentally unfriendly, economically unsustainable, and would invariably lead to animals that remained always susceptible. For example, it was observed in Zimbabwe that large farms applying acaricides very frequently (more than 30 times per annum) had higher morbidity and mortality than farms applying acaricides less frequently. Vaccination is based on infection and treatment regimen that was first developed more than 50 years ago. It involves an intravenous injection of virulent organisms in cryopreserved sheep blood, followed by treatment with tetracyclines at the first indication of fever. Most control programmes in enzootic areas are based on increasing the resistance of the population by immunization. In any vaccination programme, particular attention should be paid to the animals at high risk, particularly animals brought in from non-enzootic areas, those in surrounding similar areas to which infection may be spread by expansion of the vector population under the influence of suitable climatic conditions, and animals within the area are likely to be exposed to climatic or nutritional stress [51].
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Vaccination may lead to some deaths, the immunity may wane in the absence of reinfection, and animals may become carriers. More recently, cattle were successfully immunized for up to 10 months with a killed vaccine from a lysate of E. ruminantium formulated in Freund’s adjuvant. In another study, the use of inactivated vaccines from cell-cultured E. ruminantium combined with an adjuvant led to a reduction in mortality from heartwater in cattle, sheep and goats exposed to field challenges in Botswana, Zambia, Zimbabwe, and South Africa. Experimental studies using deoxyribonucleic acid (DNA) recombinant vaccines so far have met with only limited success. Killed A. marginale are usually in an adjuvant vehicle. The vaccine requires two doses, 4 weeks apart, the last dose given at least 2 weeks before the vector season. However, there is a risk for neonatal isoerythrolysis. This can be reduced by vaccinating only empty cows and avoiding unnecessary booster injections. When this vaccine is used in the face of an outbreak, tetracyclines can also be given to provide temporary protection during the period of development of immunity; tetracyclines do not interfere with the development of this immunity. Preliminary reports of the efficacy of DNA vaccines are not encouraging. A living A. centrale vaccine is used extensively in Australia, Africa, Israel and Latin America, but not in the USA and there is some reluctance to introduce it into areas where A. centrale does not already occur. A single vaccination is used in endemic areas and the immunity is reinforced by continuous challenge and considered to persist for life in tick areas. Vaccine administration is limited to the relatively resistant age group below 1 year of age, to the winter months when vectors are sufficiently rare to avoid the chance of spread to other age groups, and to circumstances where animals that react severely can be restrained and treated adequately. The method has the serious disadvantage of creating a large population of carrier animals which may subsequently spread the disease. Attenuated vaccines have been attempted by irradiation of strains and passage of the organism through sheep or deer and the use of naturally low virulence isolates [52, 53].
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For tick control, flumenthrin 1% pour on at 45 days interval was found to provide effective protection of Friesian/Zebu crossbred cattle against important ticks, but it must be applied correctly at the recommended dose. Pure Zebu and N\'Dama cattle would probably require less frequent applications, Flumenthrin pour-on is gradually replacing plunge dipping for the control of ticks and tick-borne diseases in general. Other than routine surveillance, there are no special biosecurity concerns with heartwater, since transmission requires the presence of the vector [54].
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2.5. Tularemia
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The disease causes acute septicaemia, with localization and granulomatous lesions and the organs (particularly the liver and spleen). Signs are very non-specific, as expected with bacteraemia, and include fever, anorexia, lethargy, and in some cases cough, rapid respiration or diarrhoea. Stiffness and oedema of the limbs may be seen. The incubation period of the disease is usually 2–14 days in companion animals [55].
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Tularemia is a highly contagious disease occurring principally in wild animals but it may transmit to farm animals, causing septicaemia and high mortality. Francisella tularensis is the causative organism [56].
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Tularemia is primarily restricted in its occurrence to countries in the northern hemisphere and occurs in most of them. In North America, the disease is most prevalent in farm animals in the north-western states of the USA and the adjoining areas of Canada, although in these areas it is rare and the majority of reports in livestock are historical. F. tularensis has a wide host range and is recorded in over 100 species of bird and wild and domestic animal. Disease is recorded among farm animals, most commonly in sheep and pigs and to a lesser extent in calves, which appear more resistant but can be infected in association with heavy tick infestation [57]. Sheep and pigs of all ages are susceptible but most losses occur in lambs, and in pigs clinical illness occurs only in piglets. There is a sharp seasonal incidence, the bulk of cases occurring during the spring months. The morbidity rate in affected flocks of sheep is usually about 20% but may be as high as 40%, and the mortality rate may reach 50%, especially in young animals. With sheep, transmission occurs chiefly by the bites of the wood tick, Dermacentor andersoni, and from Haemaphysalis otophila, the ticks becoming infected in the early part of their life cycle when they feed on rodents. In Europe Ixodes ricinus and Dermacentor reticulatus are vectors [58]. Transstadial and transovarial transmission occurs in the tick. The adult ticks infest sheep, and pastures bearing low shrubs and brush are particularly favourable to infestation. The ticks are found in greatest numbers on the sheep around the base of the ears, the top of the neck, the throat, axillae and udder. It is assumed that sheep are relatively resistant to tularemia but become clinically affected when the infection is massive and continuous. Transmission to pigs and horses is thought to occur chiefly by tick bites but mechanical transmission to laboratory animals does occur with tabanid and blackflies. Tularemia is an acute septicaemia but localization occurs, mainly in the parenchymatous organs, with the production of granulomatous lesions [59].
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In the sheep, the incubation period has not been determined. A heavy tick infestation is usually evident. The onset of the disease is slow with a gradually increasing stiffness of gait, dorsiflexion of the head and a hunching of the hindquarters; affected animals lag behind the group. The pulse and respiratory rates are increased, the temperature is elevated up to 42°C (107°F), and a cough may develop. There is diarrhoea, the faeces being dark and fetid, and urination occurs frequently with the passage of small amounts of urine. Body weight is lost rapidly, and progressive weakness and recumbency develop after several days, but there is no evidence of paralysis, the animal continuing to struggle while down [60]. Death occurs usually within a few days but a fatal course may be as long as 2 weeks. Animals that recover commonly shed part or the entire fleece but are solidly immune for long periods. In pigs, the disease is latent in adult pigs but young piglets show fever up to 42°C, accompanied by depression, profuse sweating and dyspnoea. The incubation period of the disease is about 7–10 days. In horses, fever (up to 42°C) and stiffness and oedema of the limbs occur. Foals are more seriously affected and may show dyspnoea and incoordination in addition to the above signs [61]. Necropsy usually reveals ticks on the carcass. Often, reddened or necrotic areas appear in and under the skin at the site of the infected bites. Regional lymph nodes may be swollen and congested. Congestion and oedema of the lungs are common [62].
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An agglutination test is available for the diagnosis of tularemia, a titre of 1:50 being regarded as a positive test in pigs. Serum from pigs affected with brucellosis does not agglutinate tularemia antigen, but serum from pigs affected with tularemia agglutinates brucellosis antigen. Cross-agglutination between F. tularensis and Brucella abortus is less common in sheep and an accurate diagnosis can be made on serological grounds because of the much greater agglutination that occurs with the homologous organism. Titres of agglutinins in affected sheep range from 1:640 to 1:5000 and may persist at levels of 1:320 for up to 7 months. A titre of 1:200 is considered as positive in sheep. In horses the titres revert to normal levels in 14–21 days. An intradermal sensitivity test using ‘tularin’ has been suggested as being more reliable as a diagnostic aid in pigs than the agglutination test, but is unreliable in sheep. In sheep, large numbers of ticks may be present on the hides of fresh carcasses. In animals that have been dead for some time, dark red subcutaneous areas of congestion up to 3 cm in diameter are found and may be accompanied by local swelling or necrosis of tissues [63]. These lesions mark the attachment sites of ticks. Enlargement and congestion of the lymph nodes draining the sites of heaviest tick infestation are often noted. Pulmonary oedema, congestion or consolidations are inconstant findings. In pigs, the characteristic lesions are pleuritis, pneumonia and abscessation of submaxillary and parotid lymph nodes. The organisms can be isolated from the lymph nodes and spleen, and from infected ticks. Isolation can also be effected by experimental transmission to guinea pigs. Techniques such as immunoperoxidase staining of fixed specimens and PCR of fresh tissues can circumvent the need for culture of this zoonotic agent. Samples for confirmation of diagnosis are based on
Histology: above tissues plus liver, fixed in formalin [64].
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Treatment early in the course of infection is effective. Aminoglycosides, tetracyclines or cephalosporins all are probably beneficial initially, until results of antimicrobial susceptibility testing are available. Streptomycin, gentamicin, the tetracyclines and chloramphenicol are effective treatments in humans and companion animals. Oxytetracycline (6–10 mg/kg BW) has been highly effective in the treatment of lambs and much more effective than penicillin and streptomycin. Insecticide removal of ticks from affected animals and herdmates is important. An outbreak of tularemia in sheep can be rapidly halted by spraying or dipping with insecticide to kill the vector ticks. In areas where ticks are enzootic, sheep should be kept away from shrubby, infested pasture or sprayed regularly during the months when the tick population is greatest. An experimental live attenuated vaccine has been developed, but there is no routine vaccination of livestock [65].
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\n
\n
3. Conclusion
\n
Given that the livestock industry has become an integral part of world economy and a large number of dairy cattle are being imported between countries, in order to meet an increasing demand of meat and dairy products, it is essential to review current status of bovine BTBDs and to identify diagnosis and prevention in the knowledge of BTBDs and their control. Although there has been a recent increase in the number of studies of BTBDs in various regions and facilities, information on their prevalence, distribution, tick vectors and control is limited. This chapter provides a brief background on key bovine BTBDs and ticks and reviews the general aspects of bovine BTBDs to identify gaps in knowledge and understanding of these diseases, propose areas for future research and draw attention to the need for improved tools for the diagnosis and control of BTBDs.
\n
\n\n',keywords:"tick, bacterial zoonoses, Q fever, rickettsiosis, borreliosis, ehrlichiosis, anaplasmosis, tularemia",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/53030.pdf",chapterXML:"https://mts.intechopen.com/source/xml/53030.xml",downloadPdfUrl:"/chapter/pdf-download/53030",previewPdfUrl:"/chapter/pdf-preview/53030",totalDownloads:1355,totalViews:1112,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"June 28th 2016",dateReviewed:"October 3rd 2016",datePrePublished:null,datePublished:"January 11th 2017",dateFinished:"November 17th 2016",readingETA:"0",abstract:"Bacterial tick-borne diseases (BTBDs) are very significant in practical one health medicine. In contrast to the restrictions related to diagnostic and clinical application, the control and prevention of bacterial tick-borne diseases are difficult because they require the disruption of a complicated transmission chain, involving vertebrate hosts and ticks, which interact in a constantly changing environment. Q fever, rickettsiosis, borreliosis, ehrlichiosis, anaplasmosis and tularemia are BTBDs, which are discussed in this chapter. Epidemiology, clinical symptoms, diagnosis and prevention subtopics are planning to be prepared under main topics. This chapter presents a brief background of key livestock BTBDs and ticks and reviews the general aspects of BTBDs to identify topics in knowledge and understanding of these diseases, propose areas for future research and draw attention to the need for improved tools for the diagnosis and control of BTBDs.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/53030",risUrl:"/chapter/ris/53030",book:{slug:"livestock-science"},signatures:"Şükrü Kirkan, Göksel Erbaş and Uğur Parin",authors:[{id:"194136",title:"Prof.",name:"Sukru",middleName:null,surname:"Kirkan",fullName:"Sukru Kirkan",slug:"sukru-kirkan",email:"skirkan@adu.edu.tr",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Bacterial tick-borne diseases of livestock animals",level:"1"},{id:"sec_2_2",title:"2.1. Q fever",level:"2"},{id:"sec_3_2",title:"2.2. Rickettsiosis",level:"2"},{id:"sec_4_2",title:"2.3. Borreliosis",level:"2"},{id:"sec_5_2",title:"2.4. Ehrlichiosis and anaplasmosis",level:"2"},{id:"sec_6_2",title:"2.5. Tularemia",level:"2"},{id:"sec_8",title:"3. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:' Maurin M, Raoult D. Q fever. Clin. Microbiol. Rev. 1999;12:518–553.'},{id:"B2",body:' Raoult D, Marrie TJ, Mege JL. Natural history and pathophysiology of Q fever. Lancet Infect. Dis. 2005;5:219–26.'},{id:"B3",body:'Mertens K, Samuel JE. Bacteriology of Coxiella. In: Raoult D, Parola P, editors. Rickettsial Diseases. New York: Informa Healthcare Inc.; 2007. pp. 257–270.'},{id:"B4",body:' Marrie TJ, Raoult D. Update on Q fever, including Q fever endocarditis. Curr. Clin. Top. Infect. Dis. 2002;22:97–124.'},{id:"B5",body:' Stein A, Raoult D. Pigeon pneumonia in Provence. A bird borne Q fever outbreak. Clin. Infect. Dis. 1999;29:617–620.'},{id:"B6",body:' Stoker MG, Marmion BP. The spread of Q fever from animals to man. The natural history of a rickettsial disease. 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Ability of experimentally infected chickens to infect ticks with the Lyme disease spirochete, Borrelia burgdorferi. Am. J. Trop. Med. Hyg. 1996;54:294–298.'},{id:"B37",body:'Kurtenbach K, Peacey M, Rijpkema SGT, Hoodless AN, Randolph SE Nuttall PA. Differential transmission of genospecies of Borrelia burgdorferi sensu lato by game birds and small rodents in England. App. Environ. Microbiol. 1998;64:1169–1174.'},{id:"B38",body:'Butler CM, Houwers DJ, Jongejan F, van der Kolk JH. Borrelia burgdorferi infections with special reference to horses. A review. Vet. Quart. 2005;27:146–156.'},{id:"B39",body:'O’Connor TP, Esty KJ, Hanscom JL, Shields P, Philipp MT. Dogs vaccinated with common Lyme disease vaccines do not respond to IR6, the conserved immunodominant region of the VlsE surface protein of Borrelia burgdorferi. Clin. Diag. Lab. Immunol. 2004;11:458–462.'},{id:"B40",body:'Korenberg EI, Moskvitina GG. Interrelationships between different Borrelia genospecies and their principal vectors. J. Vector Ecol. 1996;21:178–185.'},{id:"B41",body:'Littman MP, Goldstein RE, Labato MA, Lappin MR, Moore GE. ACVIM small animal consensus statement on Lyme disease in dogs: diagnosis, treatment, and prevention. J. Vet. Int. Med. 2006;20:422–434.'},{id:"B42",body:'Anonymous [Internet]. 2013. Ehrlichiosis and Anaplasmosis: Zoonotic Species Available from: http://www.cfsph.iastate.edu/Factsheets/pdfs/ehrlichiosis.pdf [Accessed: 2016-08-12]'},{id:"B43",body:'Parola P, Raoult D. Ticks and tickborne bacterial diseases in humans: an emerging infectious threat. Clin Infect Dis 2001;32:897–928. Erratum: Clin. Inf. Dis. 33:749.'},{id:"B44",body:'Raoult D, Roux V. Rickettsioses as paradigms of new or emerging infectious diseases. Clin. Microbiol. Rev. 1997;10:694–719.'},{id:"B45",body:'Anonymous [Internet]. 2012. Available from: http://www.bada-uk.org [Accessed: 2016-08-13]'},{id:"B46",body:'Cunha B, Domachowske J, Keim SM, Abuhammour W, Bennett NJ. Ehrlichiosis [Internet]. 2012. Available from: http://emedicine.medscape.com/infectious_diseases [Accessed: 2016-06-13]'},{id:"B47",body:'Dumler JS, Barbet AF, Bekker CP, Dasch GA, Palmer GH, Ray SC, Rikihisa Y, Rurangirwa FR. Reorganization of genera in the Families Rickettsiaceae and Anaplasmataceae in the order Rickettsiales: unification of some species of Ehrlichia with Anaplasma, Cowdria with Ehrlichia, and Ehrlichia with Neorickettsia, descriptions of five new species combinations and designation of Ehrlichia equi and “HGE agent” as subjective synonyms of Ehrlichia phagocytophila. Int. J. Syst. Evol. Microbiol. 2001;51:2145–2165.'},{id:"B48",body:'OIE, Terrestrial Manual. [Internet]. 2015. Available from: http://www.oie.int/fileadmin/Home/eng/Health_standards/tahm/2.04.01_BOVINE_ANAPLASMOSIS.pdf [Accessed: 2016-06-21]'},{id:"B49",body:'Alberti A, Zobba R, Chessa B, Addis MF, Sparagano O, Pinna Parpaglia ML, Cubeddu T, Pintori G, Pittau M. Equine and canine Anaplasma phagocytophilum strains isolated on the island of Sardinia are phylogenetically related to pathogenic strains from the United States. Appl. Environ. Microbiol. 2005;71:6418–6422.'},{id:"B50",body:'Uilenberg G. Note sur les babésioses et l\'anaplasmose des bovins à Madagascar. IV. Note additionelle sur la transmission. Rev. Élev. Méd. Vét. Pays Trop. 1970;23:309–312.'},{id:"B51",body:'Connell M, Hall WTK. Transmission of Anaplasma marginale by the cattle tick Boophilus microplus. Aust. Vet. J. 1972;48:477.'},{id:"B52",body:'Leatch G. Preliminary studies on the transmission of Anaplasma marginale by Boophilus microplus. Aust. Vet. J. 1973;49:16–19.'},{id:"B53",body:'Anonymous, Tick-borne Livestock Diseases and Their Vectors. [Internet]. 2016. Available from: http://www.fao.org/docrep/004/x6538e/X6538E02.htm [Accessed: 2016-06-23]'},{id:"B54",body:'MERCK, Anaplasmosis. [Internet]. 2016. Available from: http://www.merckvetmanual.com/mvm/circulatory_system/blood_parasites/anaplasmosis.Html [Accessed: 2016-06-24]'},{id:"B55",body:'Mchardy N. Immunization against anaplasmosis: a review. Prev. Vet. Med. 1984;2:135–146.'},{id:"B56",body:'Kocan KM, DE LA Fuente J, Guglielmone AA, Melendéz RD. Antigens and alternatives for control of Anaplasma marginale infection in cattle. Clin. Microbiol. Rev. 2003;16:698–712.'},{id:"B57",body:'Ellis J, Oyston PCF, Green M, Titball RW. Tularemia, Clin. Microbiol. Rev. 2002:15;631–646.'},{id:"B58",body:'OIE, Terrestrial Manual. [Internet]. 2008. Available from: http://web.oie.int/fr/normes/mmanual/2008/pdf/2.01.18_TULAREMIA.pdf [Accessed: 2016-06-29]'},{id:"B59",body:'MERCK, Overview of Tularemia. [Internet]. 2016. Available from: http://www.merckvetmanual.com/mvm/generalized_conditions/tularemia/overview_of_tularemia.html [Accessed: 2016-06-30]'},{id:"B60",body:'Bell JF. Tularaemia. In: Steel JH, editor. CRC Handbook Series in Zoonoses. Section A: Bacterial, Rickettsial, and Mycotic Diseases. 2nd ed. Florida: CRC Press; 1980. pp. 161–193.'},{id:"B61",body:'Morner T, Addison E. Tularemia. In: Williams ES, Barker IK, editors. Infectious Diseases of Wild Mammals. 3rd ed. Iowa: Iowa State University Press; 2001. pp. 303–313.'},{id:"B62",body:'Smith BP. Large Animal Internal Medicine. 4th ed. Missouri: Elsevier Health Sciences; 2008. 1184 p.'},{id:"B63",body:'AVMA, Tularemia. [Internet]. 2016. Available from: https://www.avma.org/News/Journals/Collections/Documents/javma_222_6_725.pdf [Accessed: 2016-07-02]'},{id:"B64",body:'Anonymous. Tularemia, Kosovo. Wkly. Epidemiol. Rec. 2000;75:133–134.'},{id:"B65",body:'Gilligan PH. Pseudomonas and Burkholderia. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. 6th ed. Manual of Clinical Microbiology. Washington DC: American Society for Microbiology Press; 1995. pp. 509–519.'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Şükrü Kirkan",address:"skirkan@adu.edu.tr",affiliation:'
Department of Microbiology, Faculty of Veterinary Medicine, Adnan Menderes University, Aydin, Turkey
Department of Microbiology, Faculty of Veterinary Medicine, Adnan Menderes University, Aydin, Turkey
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\n
1. Introduction
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Nanofibrous scaffolds are one of the most promising materials for skin tissue engineering and wound dressing, because they resemble nanoarchitecture of the native extracellular matrix (for a review, see [1]). Therefore, they can serve as suitable carriers of cells for tissue engineering and also as suitable wound dressings, which are able to protect the wound from external harmful effects, mainly microbial infection, and at the same time, they can keep appropriate moisture and gas exchange at the wound site.
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Nanofibrous scaffolds for skin tissue engineering have been fabricated from a wide range of synthetic and nature-derived polymers, which can be either biostable or degradable within the human body. Biostable synthetic polymers used in nanofiber-based skin regenerative therapies include, for example, polyurethane [2], polydimethylsiloxane [3], polyethylene terephthalate [4], polyethersulfone [5], and also hydrogels such as poly(acrylic acid) (PAA, [6]), poly(methyl methacrylate) (PMMA, [7]), and poly[di(ethylene glycol) methyl ether methacrylate] (PDEGMA, [8]). Degradable synthetic polymers typically include poly(ε-caprolactone) (PCL, [9]) and its copolymers with polylactides (PLCL, [10]), polylactides (PLA, [11]) and their copolymers with polyglycolides (PLGA, [12]), and also so-called auxiliary polymers, such as poly(ethylene glycol) (PEG), poly(ethylene oxide) (PEO, [13]) or poly(vinyl alcohol) (PVA, [14]), which facilitated the electrospinning process and improved the mechanical properties and wettability of the chief polymer. However, the synthetic polymers, although they are well-chemically defined and tailorable, are often bioinert, hydrophobic and thus not promoting cell adhesion, and also not well-adhering to the wound site. Therefore, they need to be combined with other bioactive substances, particularly nature-derived polymers.
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This chapter is focused on nature-derived polymers used for fabrication of nanofibrous scaffolds for skin tissue engineering and wound healing. The advantages of most of these polymers are their better bioactivity, flexibility, wettability, and adhesion to the wound site. Similarly as synthetic polymers, also nature-derived polymers can be divided into polymers with none or limited degradability, when implanted into human tissues, and polymers well-degradable in human tissues. The first group includes glucans, such as cellulose, schizophyllan, dextran, starch, and other polysaccharides and proteins, such as pullulan, xylan, alginate, pectin, gum tragacanth, gum arabic, silk fibroin, and sericin. The second group of polymers degradable in human tissues includes collagen and its derivative gelatin, elastin, keratin, glycosaminoglycans such as hyaluronic acid, heparin and chondroitin sulfate, and also polymers not produced in the human body, namely chitosan, gellan gum, zein, and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV).
\n
Some of the polymers degradable in human tissues, such as collagen, gelatin, elastin, keratin, and glycosaminoglycans, contain specific cell-binding motifs in their molecules, for example, specific amino acid sequences in proteins and oligosaccharide domains in glycosaminoglycans, which are recognized by cell adhesion receptors of integrin and non-integrin families (for a review, see [15, 16]). These molecules are often used in allogeneic or xenogeneic form, thus they can be associated with pathogen transmission or immune reaction. However, some synthetic polymers, for example PLA and PCL, have been reported to induce a more pronounced inflammatory reaction than gelatin [17].
\n
This review chapter summarizes earlier and recent knowledge on skin tissue engineering and wound dressing applications, based on nanofibrous scaffolds made of nature-derived polymers, including our results.
\n
\n
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2. Nature-derived nanofibers with none or limited degradability in the human tissues
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Nature-derived nondegradable polymers or polymers with limited degradability in human tissues include polymers not occurring in the human body and synthesized by other organisms, such as plants, algae, fungi, insects, and bacteria.
\n
\nCellulose is a typical natural polymer nondegradable in human tissues. Cellulose belongs to the group of glucans, that is, polysaccharides derived from D-glucose, linked by glycosidic bond. In the cellulose molecules, these glycosidic bonds are of the β-type, thus the cellulose is a β-glucan. It is structural polysaccharide consisting of a linear chain of several hundred to over ten thousand β(1 → 4) linked D-glucose units. Cellulose is synthesized by plants, algae, fungi, some species of bacteria (Gluconacetobacter xylinus), and also by some animals, namely tunicates (Styela clava) (for a review, see [18, 19]).
\n
Nanofibrous cellulose can be prepared in three basic forms: bacterial cellulose, which contains cellulose nanofibrils, synthesized by bacteria, nanofibrillar cellulose prepared from plants, particularly from wood, by hydrolysis, oxidation, and mechanical disintegration, and cellulose nanofibers created by electrospinning (for a review, see [19]). For electrospinning, cellulose should be solved. Well-known solvent of cellulose is N-methylmorpholine-N-oxide (NMMO). Another possibility is N-alkylinidazolium-derivate ionic liquid and N,N-dimethylacetamide containing 8 wt% of LiCl. However, any of them did not prove to be a good solvent for needleless electrospinning. The most favorable solvent of cellulose was found to be trifluoroacetic acid (TFA). However, TFA causes severe skin burns and is toxic for aquatic organisms even in low concentrations [20]. These problems, which limit the use of cellulose for creation of electrospun scaffolds for biomedical applications, can be solved by substituting the natural cellulose by its derivatives. The mostly used derivative of cellulose is cellulose acetate (CA), mainly due to its easier solubility and biocompatibility. CA can be dissolved in several solvents, however the best ones for electrospinning proved to be acetic acid (AA), and mixtures of acetone and N,N-dimethylacetamide (DMAC). Some results of successfully spun fibers by needleless electrospinning in our experiments can be found in \nFigure 1\n, demonstrating differences in the fiber morphology. The 95% aqueous mixture of AA showed the best results in comparison with acetone/DMAC mixtures due to production of smoother fibers and lower cytotoxicity.
\n
Figure 1.
Scanning electron microscopy of nanofibrous layers produced by wire needleless electrospinning using different solvents, namely 12 wt% of CA in acetone/DMAC (9:1) (left) or 14 wt% of CA in 95% AA (right).
\n
All the mentioned forms of cellulose have been widely applied as wound dressings releasing various bioactive agents into wounds (antimicrobial, anti-inflammatory, antioxidative agents, cytokines, and growth and angiogenic factors), as transparent wound dressings for direct optical monitoring of wounds, for systemic transdermal drug delivery (analgesics, antiphlogistics, corticoids, and antihypertensives) and for construction of epidermal electronics for monitoring wound healing or physiological status of the organism. Non-degradable nanocellulose has also been used as a temporary carrier for delivery of keratinocytes, dermal fibroblasts, and mesenchymal stem cells into wounds (for a review, see [19]).
\n
However, for use as direct scaffolds for skin tissue engineering, cellulose should be rendered degradable in human tissues. Cellulose is degradable by cellulase enzymes (exoglucanases and endoglucanases), which hydrolyze 1,4-beta-D-glycosidic linkages. These enzymes are not synthesized in human tissues, but they can be incorporated into cellulose scaffolds in order to degrade them gradually [21, 22]. These enzymes are believed to be non-toxic for mammalian cells [23, 24]. Moreover, the final product of cellulose degradation by these enzymes is glucose, which is a natural nutrient for the cells, by contrast with the acidic by-products of the standard currently used biodegradable PLA or PLGA scaffolds [25]. Another possibility how to use cellulase enzymes in skin tissue engineering (and in tissue engineering in general) is cell sheet technology. First, cells can be grown on the top of non-degradable cellulose substrates. After reaching the cell confluence, self-standing cell sheets can be released by exposure of the cellulose substrates to cellulases. Unlike the proteolytic enzymes conventionally used for detaching cells from their growth supports, cellulases do not disintegrate the extracellular matrix (ECM) formed by cells and do not cleave extracellular parts of cell adhesion receptors binding the ECM [26]. The cell sheets can be then replanted in the wound bed.
\n
Another interesting approach how to render the cellulose degradable was metabolic engineering of Gluconacetobacter xylinus, which then produced modified cellulose molecules with intercalated N-acetylglucosamine (GlcNAc) residues, susceptible to degradation with lysozyme, present in the human body. After subcutaneous implantation in mice, the modified cellulose was completely degraded within 20 days [27, 28].
\n
Other approaches how to render the cellulose degradable, at least partially, is its oxidation and other chemical modifications of cellulose, such as its conversion into regenerated cellulose or 2,3-dialdehydecellulose. In addition, cellulose of animal origin, that is, from tunicates, degraded more quickly than plant cellulose. For example, when cellulose films from Styela clava were implanted subcutaneously into rats for 90 days, they lost almost 24% of their initial weight, while the films prepared from wood pulp cellulose lost only less than 10% (for a review, see [19]).
\n
\nSchizophyllan is another β-glucan used for potential wound healing application. It is an extracellular β-1,3 beta-glucan with β-1,6 branching, produced by the fungus Schizophyllum commune. In blends with PVA, it was used for electrospinning of nanofibrous scaffolds, which provided a suitable growth support for human dermal fibroblast. In experimental wound models in vivo, schizophyllan attracted macrophages, necessary for the first physiological phase of wound healing, that is, inflammation. Schizophyllan and other 1,3-β-glucans also increased collagen deposition, cellularity, formation of granulation tissue, and vascularity at the wound site [29].
\n
Other glucans used for fabrication of nanofibrous scaffolds for skin tissue engineering and wound healing include dextran, starch and pullulan. According to the type of their glycosidic bonds, these polysaccharides belong to α-glucans.
\n
\nDextran is a branched complex glucan, in which the D-glucose units are linked by α-1,6 glycosidic bonds with branches from α-1,3 linkages. Dextran is of microbial origin; it can be produced, for example, by some lactic acid bacteria from sucrose. Dextran was used as a component of nanofibrous polyurethane-based wound dressings, in which dextran promoted neovascularization of the wound site, and also served as carrier for β-estradiol, an endogenous estrogen, a potent anti-inflammatory agent, and mitogen for keratinocytes. In addition, the presence of dextran made the polyurethane dressing softer, more flexible, more wettable, and well-adherent to the wound and promoted hemostatic activity of the dressing. In vitro, the presence of dextran and β-estradiol enhanced the proliferation of 3T3-L1 fibroblasts on the scaffolds [30].
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Dextran was also used as component of a bilayer scaffold for skin tissue engineering. The upper part of the scaffolds was made of electrospun blend of poly(ε-caprolactone-co-lactide) and poloxamer (i.e., Pluronic), and the lower part was made of a hydrogel composed of dextran and gelatin without the addition of a chemical crosslinking agent. The lower dextran/gelatin hydrogel layer provided a highly swollen three-dimensional environment similar to extracellular matrix (ECM) of soft tissues. Both part of the scaffolds supported the growth of adiposetissue-derived stem cells; however, the number of these cells on the hydrogels decreased with increasing content of dextran [31].
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Dextran is degradable by dextranases, enzymes hydrolyzing (1 → 6)-alpha-D-glycosidic linkages. This enzyme is produced mainly by bacterial and fungi, but it was also detected in animal and human tissues, namely liver and spleen. Therefore, dextran is often chosen for biomedical applications, particularly drug delivery, because it is slowly degradable in human organism. Dextran molecules with Mw higher than 40 kDa are sequestered in the liver and spleen, and then hydrolyzed by endo- and exodextranases. Dextran molecules with Mw lower than 40 kDa can be eliminated through renal clearance [32]. However, dextran hydrogels implanted subcutaneously or intramuscularly into rats did not show signs of degradation 6 weeks post-implantation and were surrounded by a thin fibrous capsule and some macrophages and giant cells, which is a response typical for a number of non-degradable materials [32].
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\nStarch is another α-glucan, containing both α-1,4- and α-1,6 glycosidic bonds. It serves an energy storage polysaccharide in plants, and from this point of view, it is considered to be an analogue of glycogen, energy storage polysaccharide in animals. Starch consists of two types of molecules, namely linear amylose and branched amylopectin (for a review, see [33]). Electrospun starch-based nanofibrous meshes were proposed for wound healing applications. The electrospinning of starch was facilitated by addition of PVA, that is, a noncytotoxic, water-soluble, biocompatible synthetic polymer which reduced the repulsive forces produced in starch solution. The scaffolds then promoted the proliferation of mouse L929 fibroblasts [34]. Starch is degradable by amylases, that is, hydrolases that act on α-1,4-glycosidic bonds. Amylases occur in three forms, namely α-, β-, and γ-amylases. These enzymes are synthesized by microorganisms (bacteria and fungi), plants, and with exception of β-amylases, also in animals. Alpha-amylases are present in human organism, but not currently in all tissues-they are important enzymes of gastrointestinal tract and are produced by salivary glands and pancreas. Interestingly, α-amylases were also found in brain, and their lower expression there is probably associated with the pathogenesis of Alzheimer’s neurodegenerative disease [35].
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\nPullulan is also an α-glucan with both α-1,4- and α-1,6 glycosidic bonds. It is a linear polysaccharide consisting of maltotriose units, in which three glucose units in maltotriose are connected by an α-1,4 glycosidic bond, whereas consecutive maltotriose units are connected to each other by an α-1,6 glycosidic bond. Pullulan is produced from starch by the fungus Aureobasidium pullulans. It shows a high water-absorbing capability, adhesive properties, and the capability to form strong resilient films and fibers. It is degradable by pullulanase, a specific kind of glucanase, produced in bacteria and not present in human tissues. When pullulan hydrogels alone or in combination with dextran were implanted subcutaneously into rats, they induced inflammatory reaction and were surrounded by a fibrous capsule [36]. Nevertheless, pullulan is water-soluble and thus removable from human issues, and in combination with chitosan and tannic acid, it was used for fabrication of electrospun nanofibrous meshes promising for wound healing [37]. In combination with dextran and gelatin, pullulan was used for electrospinning of nanofibrous scaffolds promising for skin tissue engineering. These scaffolds, especially when crosslinked with trisodium trimetaphosphate, supported the adhesion and spreading of human dermal fibroblasts and formation of actin cytoskeleton in these cells [38].
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\nXylan is a plant polysaccharide belonging to the group of hemicelluloses, that is, polymers often associated with cellulose. While cellulose is made of glucose units, hemicelluloses contain many different sugar monomers. Xylans are polysaccharides made of β-1,4-linked xylose (i.e., a pentose sugar) residues with side branches of α-arabinofuranose and α-glucuronic acids, which contribute to crosslinking of cellulose microfibrils and lignin through ferulic acid residues. Xylans are considered as relatively available and cost-effective natural materials for tissue engineering. Electrospun nanofibers containing beech-derived xylan and PVA were tested as potential dermal substitutes for skin tissue regeneration. These scaffolds provided a good support for the adhesion and proliferation of human foreskin fibroblasts and for production of collagen by these cells [39]. Bagasse xylan was also a component of hydrogels endowed with shape memory, namely carboxymethyl xylan-g-poly(acrylic acid) hydrogels, applicable in tissue engineering and biosensorics, particularly for construction of electronic skin [40].
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\nAlginates, for example, sodium alginate or calcium alginate, are salts of alginic acid, a linear polysaccharide composed of (1,4)-β-D-mannuronic acid and (1,3)-α-L-guluronic acid. Alginates are produced by various species of brown algae, and also by the bacterium Pseudomonas aeruginosa, a major pathogen found in the lungs of patients with cystic fibrosis. The structure of alginates is similar to glycosaminoglycans, an important component of ECM in human tissues including skin [41]. Alginates have a great ability to keep moisture in the wound site and to adhere to skin. However, alginates are poorly spinnable, and therefore, for skin tissue engineering and wound dressing applications, they were electrospun together with other polymers, such as PVA [41, 42] or PEO [43]. Poor mechanical properties of alginates have been compensated by the combination with chitosan [44] or PCL [44, 45]. In addition, alginates themselves are not adhesive for mammalian cells, which was compensated by their combination with collagen and gelatin, containing ligands for cell adhesion receptors [41]. Alginates were modified with a cell adhesive GRGDSP oligopeptide, which acts as ligand for integrin cell adhesion receptors [43]. Sodium alginate was used for attachment of arginine to the surface of chitosan nanofibers in order to increase healing capability of this wound dressing [46]. Alginate nanofibers supported by PCL were impregnated with an extract from Spirulina, a photosynthetic cyanobacterium producing bioactive molecules with anti-oxidant and anti-inflammatory effects [45]. Electrospun sodium alginate nanofibers containing silver nanoparticles were used for fabrication of an electronic skin capable of pressure sensing and endowed with antibacterial activity [47].
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The degradability of alginate in human organism is limited. Alginate is naturally degraded by alginate lyases or alginate depolymerases, which have been isolated from marine algae, marine animals, bacteria, fungi, viruses, and other microorganisms, but are not present in the human organism. Degradability of alginate can be increased by its oxidation and at low pH. Also the hydrophilicity and water uptake capacity of alginate can help in its removal from the wound site (for a review, see [48]).
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\nPectin is a complex of structural polysaccharides present in the cell walls of terrestrial plants, rich in galacturonic acid. Pectin is known as gelling agent in food industry, but it is also widely used in medicine, for example, against digestive disorders, such as obstipation and diarrhea, for oral drug delivery, as a component of dietary fibers trapping cholesterol and carbohydrates, as a demulcent, that is, a mucoprotective agent, and also in wound healing preparations [49]. Pectin is known as a natural prophylactic substance against poisoning with toxic cations, and its hemostatic and curing effects are well-documented in healing ointments [50]. Pectin is degradable by enzymes produced by bacterial, fungal and plant cells, and not present in human tissues [51, 52, 53]. Thus, pectin is degradable, at least partly, only in the intestinal tract populated with bacteria. However, pectin is water-soluble and quickly dissolves in the water environment, including the tissues. Therefore, in order to increase its stability, it was combined with chitosan and TiO2 nanoparticles for wound dressing applications [50] or used for construction of composite chitosan-pectin scaffolds for skin tissue engineering. Blending chitosan with pectin markedly improved the mechanical properties of the scaffolds, such as their Young’s modulus, strain at break and ultimate tensile strength, in comparison with pure chitosan scaffolds, although the proliferation of cells (i.e., fibroblasts) was slightly slower on pectin-containing scaffolds [54, 55]. The reason is that pectin does not contain cell binding domains. The cell adhesion on pectin nanofibers was markedly enhanced by oxidizing pectin with periodate to generate aldehyde groups, and then crosslinking the nanofibers with adipic acid dihydrazide to covalently connect pectin macromolecular chains with adipic acid dihydrazone linkers. In addition, the crosslinked pectin nanofibers exhibited excellent mechanical strength and enhanced body degradability [56].
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Other polysaccharides explored for creation of nanofibrous scaffolds for skin tissue engineering and wound healing are gum tragacanth and gum arabic, both polysaccharides of plant origin, degradable by bacteria and fungi, for example, in soil [57, 58].
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\nGum tragacanth is a viscous water-soluble mixture of polysaccharides, mainly tragacanthin and bassorin. Tragacanthin dissolves to give a colloidal hydrosol. Bassorin, representing 60–70% of the gum, is insoluble and swells to a gel. Chemically, tragacanthin is a complex mixture of acidic polysaccharides containing D-galacturonic acid, D-galactose, L-fucose (6-deoyl-L-galactose), D-xylose, and L-arabinose. Bassorin is probably a methylated tragacanthin. A small amount of cellulose, starch, protein and ash are also present (https://colonygums.com/tragacanth). In order to improve electrospinning and mechanical properties of the gum tragacanth, it was combined with PVA and PCL [59]. Gum tragacanth is endowed with microbial resistance and wound healing activity, which was further enhanced by curcumin, a naturally occurring poly-phenolic compound with a broad range of favorable biological functions, including anti-cancer, anti-oxidant, anti-inflammatory, anti-infective, angiogenic, and healing properties [60].
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\nGum arabic, also known as gum acacia, is a complex and water-soluble mixture of glycoproteins and polysaccharides consisting mainly of arabinose and galactose. For skin tissue engineering, it was electrospun with PCL and also with zein, a storage plant protein [61].
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\nSilk fibroin is a water-insoluble elastic protein present in silk fibers produced by larvae of Bombyx mori and some other moth of the Saturniidae family, such as Antheraea assama, Antheraea mylitta, and Philosamia ricini [62, 63, 64]. Silk fibroin occurs in the fibers together with sericin, a water-soluble serine-rich protein, which forms a glue-like layer coating two singular filaments of fibroin.
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In biomaterial science, silk fibroin is considered to be degradable, but in mammalian organism, this degradation is long-lasting and can take more than 1 year. As a kind of biomaterial approved by the Food and Drug Administration (FDA) for medical use, silk is defined by United States Pharmacopeia as non-degradable for its negligible tensile strength loss in vivo. However, silk fibroin is susceptible to biological degradation by proteolytic enzymes such as chymotrypsin, actinase, carboxylase, proteases XIV, XXI and E, and collagenase IA. The final degradation products of silk fibroin are amino acids, which are easily absorbed in vivo (for a review, see [65]).
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The degradation behavior of fibroin scaffolds depends on the preparation method and structural characteristics, such as processing condition, pore size, and silk fibroin concentration (for a review, see [65]). For example, three-dimensional porous scaffolds prepared from silk fibroin using all-aqueous process degraded within 2–6 months after implantation into muscle pouches of rats, while the scaffolds prepared using an organic solvent, hexafluoroisopropanol (HFIP), persisted beyond 1 year. It was probably due to a lower original silk fibroin concentration, larger pore size, and a higher and more homogeneous cellular infiltration of aqueous-derived scaffolds than in HFIP-derived scaffolds [66].
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For skin tissue engineering and wound healing, silk fibroin has been combined with various synthetic and natural polymers and other bioactive substances. The polymers included, for example, PCL, [67], poly(L-lactic acid)-co-poly(ε-caprolactone) (PLACL, [68]), carboxyethyl chitosan, PVA, [69], chitin [70], cellulose-based materials modified by oxidation [71] or with lysozyme [72], collagen [73], gelatin [74], and hyaluronan [75]. The bioactive substances were, for example, growth factors, such as epidermal growth factor [64], vitamins, such as vitamin C [68], vitamin E [76], and pantothenic acid (vitamin B5; [77]), antioxidants, such as grape seed extract ([78]) or quinone-based chromenopyrazole [79], antibiotics, such as ciprofloxacin [64], tetracycline [68] or gentamycin [62], and other antimicrobial and wound healing agents, such as silver nanoparticles, dandelion leaf extract [63], Aloe vera [80], or astragaloside IV [74]. In order to enlarge the pore size in nanofibrous scaffolds for cell penetration, silk fibroin was electrospun together with so-called “sacrificial” crystals of ice [67] or NaCl [81, 82], that is, crystals which are removed after the electrospinning process. An interesting combination is silk fibroin with decellularized human amniotic membrane, which was used for developing a three-dimensional bi-layered scaffold for burn treatment. Adipose tissue-derived mesenchymal stem cells seeded on this scaffold increased expression of two main pro-angiogenesis factors, vascular endothelial growth factor, and basic fibroblast growth factor [83]. Also the transplantation of bone marrow-derived mesenchymal stem cells and epidermal stem cells into wounds using nanofibrous silk fibroin scaffolds supported re-epithelization, collagen synthesis, as well as the skin appendages regeneration [84]. Another interesting approach is to use silk fibroin produced by other species than Bombyx mori, namely by the moths Antheraea assama and Philosamia ricini. This “non-mulberry” silk fibroin possesses inherent Arg-Gly-Asp (RGD) motifs in its protein sequence, which facilitates binding of cells through their integrin adhesion receptors [64].
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\nSericin has also been applied in skin tissue engineering and wound healing, although in a lesser extent than silk fibroin. Sericin shows antioxidant, UV-protective, heat-protective, moisture-retaining, and antimicrobial properties, which have been reported to be more pronounced in non-mulberry sericin (e.g., from Antheraea mylitta) than in sericin produced by Bombyx mori. The reason is that wild moths like Antheraea mylitta are exposed to a hostile environment in nature than Bombyx mori raised in captive conditions. Similarly as non-mulberry silk fibroin, also sericin has been reported to be more supportive for cell adhesion than mulberry sericin (for a review, see [85]). Sericin enhanced the proliferation and epidermal differentiation of human mesenchymal stem cells on gelatin/hyaluronan/chondroitin sulfate nanofibrous scaffolds [86]. Similarly, sericin improved the growth of murine L929 fibroblasts and human HaCaT keratinocytes cultured on the PVA nanofibrous scaffolds [87] and also the growth of L929 fibroblasts on chitosan nanofibrous scaffolds, together with antibacterial properties of these scaffolds [88].
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3. Nature-derived nanofibers degradable in the human tissues
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Nature-derived polymers degradable in human tissues include, in particular, polymers that are synthesized in the human body and usually act as components of ECM. These polymers are proteins (collagen and its derivative gelatin, elastin, fibrinogen and fibrin, keratin) or polysaccharides in non-sulfated form (hyaluronic acid) and sulfated form (heparin-like glycosaminoglycans). In addition, some natural polymers synthesized by other organisms, such as bacteria, fungi, insects, crustaceans or plants, are degradable in human tissues, because they are susceptible to enzymes present in human tissues, such as lysozyme and esterases. These polymers include chitosan, gellan gum, zein, and PHBV.
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\nCollagen is the main structural protein in the extracellular space in a wide range of tissues in the body. Skin contains type I collagen, one of the most abundant collagens in the human body. Type I collagen is also abundant in tendons, ligaments, and vasculature, and it is a main component of the organic part of bone. Type I collagen is a fibrillar type of collagen; it is composed of amino acid chains forming triple-helices of elongated fibrils. That is why the nanofibrous collagen scaffolds closely mimic the architecture of the native ECM and are advantageous for tissue engineering. In addition, collagen has been reported to be relatively poorly immunogenic, even if used in allogeneic and xenogeneic forms, for example, recombinant human collagen or bovine and porcine collagen. However, mammalian collagen is associated with the risk of disease transmission, for example, bovine spongiform encephalopathy (for a review, see [89, 90, 91]). This risk can be reduced by the use of fish collagen, which became to be popular in tissue engineering, including skin tissue engineering and wound healing. In addition, the fish collagen enables an easier recovery of intact collagen triple helices than the mammalian collagen [92]. Fish collagen can be obtained from the skin, scales and bones of freshwater fish, such as tilapia [91, 92, 93, 94], and marine fish, such as hoki fish (Macruronus novaezelandiae) [92, 95], or Arothron stellatus, also known as “stellate puffer,” “starry puffer” or “starry toadfish” [96]. Nanofiber electrospun from tilapia skin collagen promoted the proliferation of human HaCaT keratinocytes, and stimulated epidermal differentiation through the up-regulated gene expression of involucrin, filaggrin, and type I transglutaminase in these cells. Moreover, the tilapia collagen nanofibers accelerated wound healing in vivo in rat models [91, 92, 93, 94]. Beneficial effects on wound healing were also observed in nanofibrous meshes electrospun from collagen obtained from Arothron stellatus [96] and from fish scale collagen peptides [90].
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Collagen is one of the most widely used natural proteins for creation of nanofibrous scaffolds for skin tissue engineering and wound healing. However, these scaffolds are usually mechanically weak, and therefore they need crosslinking or blending with synthetic polymers. Collagen crosslinking with conventionally used agents, particularly glutaraldehyde, is associated with the risk of the scaffold cytotoxicity. More benign crosslinkers used recently include, for example, citric acid [95] or quaternary ammonium organosilane, a multifunctional crosslinking agent, which improved the electrospinnability of collagen by reducing its surface tension, endowed the collagen nanofibers with potent antimicrobial activity and promoted the adhesion and metabolic activity of primary human dermal fibroblasts without any cytotoxicity, at least in a lower concentration of 0.1% w/w [97].
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Synthetic polymers used for combination with collagen in nanofibrous scaffolds included PLA [98], PLGA [99, 100], and particularly PCL, which was either blended with collagen [101, 102, 103, 104] or served as substrate for subsequent deposition of collagen [105]. Collagen has also been combined with natural polymers, such as silk fibroin [73] or chitosan in a form of blends [106] or in a form of bilayered scaffolds, where collagen was electrospun onto the chitosan scaffolds [107]. Collagen was also grafted on the surface of composite electrospun PVA/gelatin/alginate nanofibers [41]. Collagen-based or collagen-containing nanofibers have been loaded with a wide range of bioactive substances, such as vitamin C, vitamin D3, hydrocortisone, insulin, triiodothyronine, and epidermal growth factor [100], transforming growth factor-β1 [102], plant extracts such as Coccinia grandis leaf extract [96], or lithospermi radix extract [107], antibiotics such as gentamicin [103], or bioactive glass [93, 104]. Collagen and PCL and bioactive glass nanoparticles were applied for delivery of endothelial progenitor cells into wounds in order to promote their vascularization and healing [104].
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\nGelatin is a derivative of collagen, obtained by denaturing its triple helical structure. Specifically, it is a mixture of peptides and proteins produced by partial hydrolysis of collagen extracted from the skin, bone, and connective tissue of animals, such as cattle, pigs, chicken, and also fish. Gelatin can be defined as a complex mixtures of oligomers of the α subunits joined by covalent bonds, and intact and partially hydrolyzed α-chains of varying molecular weight (for a review, see [89, 92]). Properties of gelatin, including its spinnability, depend on the source of collagen, animal species, age, type of collagen, type of conversion of collagen to gelatin (i.e., acidic vs. basic hydrolysis), and particularly on the conformation of gelatin molecules [108].
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Similarly as collagen, also gelatin is the most promising for skin tissue engineering and wound healing applications in combination with various synthetic and natural polymers. For example, gelatin was combined with polyurethane [109], PLA [11, 17], and particularly with PCL, where it was incorporated into core-shell PCL/gelatin nanofibers as the core polymer [110] or electrospun independently of PCL using a double-nozzle technique, which resulted in creation of two types of nanofibers in the scaffolds, either mixed [111] or arranged in separate gelatin and PCL layers [112]. Gelatin was also combined with a copolymer of lactic acid and caprolactone P(LLA-CL) in the form of blends [113] or in the form of coaxial nanofibers with P(LLA-CL)/gelatin shell and albumin core containing epidermal growth factor, insulin, hydrocortisone, and retinoic acid [114]. Natural proteins combined with gelatin included dextran [31], pullulan [38], alginate [41], silk fibroin [74], and hyaluronan with chondroitin sulfate [86].
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For combination with synthetic and natural polymers, for example, with PCL [115], and chitosan and keratin [116], gelatin was also used in the form of photocrosslinkable gelatin methacrylate hydrogel (GelMA). On PCL nanofibers, GelMA showed a higher decoration level in comparison with native gelatin [116]. Self-standing nanofibrous matrices electrospun from GelMA enabled tuning of their water retention capacity, stiffness, strength, elasticity, and degradation by changing the exposure time to UV light [117].
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\nElastin is a protein found in the ECM, that maintains its elasticity [118]. It is the second main protein-based component of native skin ECM. The presence of elastin in composite electrospun nanofibrous scaffolds, containing gelatin, cellulose acetate and elastin, changed the fiber morphology from straight to ribbon-like structure, and decreased the swelling ratio and degradation rate of the scaffolds. In addition, elastin-containing scaffolds supported the attachment and proliferation of human fibroblasts [119].
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\nFibrin is a provisional ECM protein, which accumulates in wounds after injury to initiate hemostasis and healing. Fibrin is formed via the polymerization of fibrinogen monomers in the presence of thrombin, and this process can be simulated in vitro [120]. Fibrin forms a fine nanofibrous mesh, which is mechanically weak and needs to be deposited on some supportive structure, for example, synthetic nanofibrous meshes made of poly(L-lactide) (PLLA) [121]. In our experiments, fibrin was deposited on PLLA in the form of two types of coating, depending on the mode of fibrin preparation. Fibrin either covered the individual fibers in the membrane (F1 nanocoating), or covered the individual fibers and also formed a fine homogeneous nanofibrous mesh on the surface of the membrane (F2 nanocoating), depending on the mode of fibrin preparation. The fibroblasts on the F1 nanocoating remained in their typical spindle-like shape, while the cells on the F2 nanocoating were polygonal with a higher proliferation rate [122]. F2 nanocoating was then used for development of a bilayer skin construct. First, a nanofibrous PLLA mesh was coated with fibrin and seeded with human dermal fibroblasts. After reaching confluence, the fibroblasts were covered with a collagen hydrogel and were allowed to migrate into this hydrogel and to proliferate inside. After sufficient colonization of the hydrogel with fibroblasts and formation of a structure resembling the skin dermis, human epidermal keratinocytes were seeded on the top of the collagen hydrogel (\nFigure 2\n) [123].
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Figure 2.
Developing a bilayer construct of keratinocytes and fibroblasts on a PLLA nanofibrous membrane with fibrin and collagen hydrogel. Left: schematic design; right: real construct.
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Also fibrinogen was used for modification of synthetic polymeric nanofibers in order to enhance the cell adhesion and growth. Nanofibrous scaffolds electrospun from blends of PCL and fibrinogen improved the adhesion, proliferation, and epidermal differentiation of adipose tissue-derived stem cells (ADSCs) in comparison with pure PCL scaffolds. Composite PCL/fibrinogen scaffolds seeded with ADSCs also markedly improved healing of full-thickness excisional wounds created in rats in comparison with acellular dermal matrix or acellular dermal matrix with ADSCs [124].
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\nKeratin is a fibrous structural protein, present in skin appendages, such as hair, wool, feather, nails, horns, claws, hooves, and in the outer (cornified) layer of epidermis [125, 126]. Keratin protects epithelial cells from damage and stress and is insoluble in water and organic solvents.
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In most studies dealing with keratin-containing nanofibers, keratin was combined with other natural or synthetic polymers in order to improve the spinnability of keratin, or to improve the bioactivity of the co-electrospun polymer. For example, in a study by Cruz-Maya et al. [127], blending keratin with PCL improved the stability of the electrospinning process, promoted the formation of nanofibers without defects, such as beads and ribbons, typically observed in the fabrication of keratin nanofibers. At the same time, keratin markedly increases the fiber hydrophilicity compared with pure PCL, which improved the adhesion and proliferation of human mesenchymal stem cells [127]. Similarly, co-electrospinning of keratose (i.e., oxidative keratin) with PVA resulted in nanofibers with uniform fibrous structure, suitable hydrophilicity and mechanical properties [125]. Properties of electrospun keratin nanofibers were also improved by incorporation of hydrotalcites, intended for delivery of diclofenac. These nanofibers displayed a reduced swelling ratio and a slower degradation profile compared to keratin-based non-woven nanofibrous mats containing free diclofenac [126]. Keratin was also a component of core-shell nanofibers, prepared by coaxial electrospinning of chitosan, PCL and keratin with Aloe vera extracts encapsulated inside the polymer nanofibers. This construct increased the adhesion and growth of L929 fibroblasts and was intended for wound healing applications [128]. Importantly, keratin was a component of bilayer scaffolds for skin tissue engineering, composed of human hair keratin/chitosan nanofiber mat and gelatin methacrylate (GelMA) hydrogel. Human dermal fibroblasts were encapsulated and grown in the hydrogel matrix, while human HaCaT keratinocytes formed a layer on the top of the scaffolds, mimicking dermis and epidermis of skin tissue [116]. Another bilayer scaffolds was constructed using polyurethane wound dressing as an outer layer, and electrospun gelatin/keratin nanofibrous mat as an inner layer [109].
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\nHyaluronic acid, also called hyaluronan, is an anionic, non-sulfated linear glycosaminoglycan. It is distributed widely throughout connective, neural, and epithelial tissues, including skin, where it is a major component of ECM. Therefore, hyaluronic acid has been widely used for skin tissue engineering and wound healing, and it is approved for clinical application [33].
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Hyaluronic acid stimulated infiltration of nanofibrous scaffold composed of hyaluronan, silk fibroin and PCL [75], and can help to promote cell proliferation [129]. Electrospinning of pure hyaluronic acid is not simple because of solubility characteristics of this polymer. Hyaluronic acid is well-soluble in water but less-soluble in most organic solvents, which can be solved by mixtures of solvents as water/ethanol or water/dimethylformamide [130]. Increasing of evaporation and decreasing of solution surface tension by the solvent mixing helps to electrospinning process. Another possibility is electrospinning of hyaluronic acid together with a suitable water-soluble polymer such as PVA [131] or PEO. The solution of pure hyaluronic acid [132] or with relatively small amount of carrier PEO was successfully spun into nanofibrous material by air-assisted electrospinning technology, that is, electroblowing [133]. For creation of nanofibrous scaffolds, hyaluronic acid was also used in combination with PCL [134], PLA [135] or gelatin, chondroitin sulfate and sericin [86].
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\nSulfated glycosaminoglycans have been relatively rarely used as components of nanofibers for skin tissue engineering and wound healing in comparison with hyaluronic acid. This group of polysaccharides include heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, and keratan sulfate (for a review, see [33]). From these polysaccharides, only heparin, heparan sulfate, and chondroitin sulfate were used as components of nanofibers for skin regenerative therapies. For example, heparin coatings on PLLA nanofibers increased the infiltration of the scaffolds with endothelial cells in vitro, and enhanced epidermal skin cell migration across the wound in a full-thickness dermal wound model in rats in vivo [136]. In a recent study by Yergoz et al. [137], a heparin-like nanofibrous hydrogel promoted regeneration of full thickness burn injury in mice. Chondroitin sulfate was used as a component of electrospun gelatin/PVA/chondroitin sulfate nanofibrous scaffolds, which supported the proliferation of human dermal fibroblasts [138], of electrospun nanofibrous composite scaffolds made of cationic gelatin/hyaluronan/chondroitin sulfate loaded with sericin, which promoted the differentiation of human mesenchymal stem cells toward epithelial lineage [86], and of electrospun gelatin/chondroitin sulfate nanofibrous scaffolds, which accelerated healing of full-thickness skin excision wounds in rats [139].
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\nChitosan is a linear polysaccharide composed of randomly distributed β-(1 → 4)-linked D-glucosamine (deacetylated unit) and N-acetyl-D-glucosamine (acetylated unit). It can be prepared by alkali treatment from chitin, a poly-N-acetyl-D-glucosamine polysaccharide, the major structural component of the exoskeleton of crustaceans (crab, shrimp), and of the cell wall of fungi and yeast [140]. Chitosan is known as biocompatible, antimicrobial, and biodegradable. In the human organism, it can be degraded by lysozyme, a hydrolytic enzyme present in various secretions such as saliva, tears, mucus, and human milk, and also in cytoplasmic granules of macrophages and polymorphonuclear neutrophils. Chitosan breakdown by lysozymes happens via the removal of glycosidic bonds between polysaccharide units in the polymer. Glucosamine and saccharide are the products of this process, which can be metabolized or stored as proteoglycans in the body.
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However, electrospinning of chitosan is difficult due to its polycationic characters. Due to the presence of amine groups in the chitosan molecule, acidic aqueous solutions are the best solvents for this polymer. The best candidates for solvent system seem to be mixture of acetic acid (AA) and formic acid (FA) or trifluoroacetic acid (TFA); however, TFA is highly toxic. Electrospinning of pure chitosan has very low productivity because it requires very concentrated polymeric solutions [141]. Therefore, for creation of nanofibrous scaffolds for skin tissue engineering, chitosan has been mixed with other natural or synthetic polymers, such as collagen [142], gelatin [143], keratin [116], cellulose [144], pectin [54, 55], silk fibroin [69], PHBV [145], PCL [142], PLA [146], PLGA [147], PEO, [148], and also with PVA, which was used in our studies (\nFigure 3\n). Chitosan has also been mixed with various nanoparticles, such as halloysite nanotubes [149], graphene oxide [150] or nanodiamonds [144]. The reason of all these mixtures was to improve the stability, spinnability, wettability, mechanical properties, and biofunctionality of chitosan-containing scaffolds for skin tissue engineering. Combination of chitosan with various polymers also enabled creation of bilayer scaffolds for reconstruction of two main skin layers, that is, epidermis containing keratinocytes and dermis containing fibroblasts [116, 142]. In order to enhance the antimicrobial and wound healing activity of chitosan, this polymer was electrospun together with extract from Henna leaves [151]. In addition, chitosan nanoparticles have been incorporated in nanofibrous scaffolds as carriers for controlled drug delivery, for example, delivery of growth factors, cytokines and angiogenic factors, such as platelet-derived growth factor [152], granulocyte colony-stimulating factor [153] or angiogenin [147]. Nanofibrous scaffolds promising for skin tissue engineering and wound healing were also prepared directly from chitin, which was electrospun either alone with further modifications with fibronectin, laminin and particularly with type I collagen [154], or in combination with silk fibroin [70].
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Figure 3.
Scanning electron microscopy of nanofibrous layers produced by needle electrospinning from PVA/chitosan solution.
\n
\nGellan gum is a water-soluble anionic polysaccharide produced by the bacterium Sphingomonas elodea (formerly Pseudomonas elodea). The repeating unit of the polymer is a tetrasaccharide, which consists of two residues of D-glucose, one of residue of L-rhamnose and one residue of D-glucuronic acid. For skin tissue engineering and wound healing, gellan gum was electrospun with PVA in order to decrease its viscosity and repulsive forces between the polyanions along the polymer chains and to increase the stability, uniformity, and structural consistency of the nanofibers in aqueous environment. The nanofibrous scaffolds were further stabilized by crosslinking with various physical, chemical, and ionic methods, such as by heat, UV irradiation, methanol, glutaraldehyde, and by calcium chloride [155]. These scaffolds supported the adhesion and growth of human dermal 3T3-L1 fibroblasts [155, 156] and human HaCaT keratinocytes [157] and provided a better support for these cells than conventionally proposed gellan-based hydrogels and dry films. In addition, these scaffolds were endowed with antimicrobial activity by incorporation with amoxicillin, and accelerated healing of full-thickness skin excision wound in rats in comparison with non-treated wounds [157]. Similarly as chitosan, gellan gum has been reported to be degradable by lysozyme [158]. Three-dimensional printed gellan gum scaffolds also showed degradation in vitro in phosphate-buffered saline (PBS) or in simulated body fluid, and the degradation rate could be modulated by changing the ratio of surface area per mass of the scaffolds [159].
\n
\nZein is the major storage protein of corn, composed of amino acids such as leucine, glutamic acid, alanine and proline, and showing good biocompatibility, flexibility, microbial resistance, and antioxidant activity [61]. Zein has been shown to degradable in vitro in PBS and also in vivo when implanted subcutaneously in rats in the form of rod-like implants [160]. However, similarly as in many other natural polymers, the application of pure zein nanofibers is limited because of poor mechanical properties of these fibers. Therefore, for skin tissue engineering and wound dressing applications, zein has been mixed with various synthetic and nature-derived polymers, such as polyurethane [161], PLA [162], PCL, hyaluronic acid, chitosan [163], and polydopamine [164], and impregnated with TiO2 nanoparticles [164] or Ag nanoparticles [161] in order to enhance the antimicrobial activity of the scaffolds.
\n
\nPoly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), is a polymer produced naturally by bacteria as a storage compound under growth-limiting conditions. It is a thermoplastic linear aliphatic polyester of polyhydroxyalkanoate type. PHBV is approved by the FDA for medical use. PHBV is biodegradable by bacterial enzymes, but it is also susceptible to hydrolytic degradation in water environment, although this degradation is relatively slow. When degradation of porous PHBV scaffolds for tissue engineering was simulated in vitro in PBS at 37°C, it lasted several months [165]. In the human body, however, the degradation of PHBV can be accelerated by nonspecific esterase and lysozyme enzymes, both present in cells of the immune system (for a review, see [165]). For biomedical application, PHBV is often used as an alternative to synthetic polymers, but it has several drawbacks, such as relatively high cost, brittleness, relatively difficult processing, and also hydrophobicity, which can hamper the cell adhesion and growth. However, PHBV is piezoelectric, which can stimulate the adhesion, growth, and phenotypic maturation of cells. Pure electrospun PHBV meshes supported the adhesion, growth, and epidermal differentiation of bone marrow mesenchymal stem cells, which was induced by an appropriate composition of cell culture media, containing epidermal growth factor, insulin, 3,3′,5-triiodo-L-thyronine (T3), hydrocortisone, and 1α, 25-dihydroxyvitamin (D3), and manifested by expression of genes for keratin, filaggrin, and involucrin, that is, an early, intermediate and late marker of keratinocyte differentiation, respectively [166]. In order to increase the attractiveness of electrospun PHBV nanofibers for the cell adhesion and growth, they were coated with collagen [167] blended with collagen [168], blended with chitosan [145] or blended with keratin [169]. Collagen-coated PHBV nanofibers alone or seeded with unrestricted somatic stem cells, isolated from umbilical cord, accelerated closure of excision wounds in rats in vivo compared to unmodified PHBV nanofibers [167]. Similar wound healing effect was also obtained with PHBV nanofibers blended with keratin [169]. Mechanical properties of PHBV nanofibers were improved by addition of graphene oxide nanoparticles in the electrospinning solution, which also endowed these fibers with and antimicrobial activity [167].
\n
\n
\n
4. Conclusions
\n
Nanofibrous scaffolds made of nature-derived polymers hold a great promise for skin tissue engineering and wound healing. These scaffolds are created from biological matrices, and from this point of view, they resemble the extracellular matrix more closely than synthetic polymers. Some of these polymers, such as collagen, gelatin, elastin, keratin, nonsulfated and sulfated glycosaminoglycans, and also nonmulberry silk fibroin, contain motifs that are recognized and bound by cell adhesion receptors. Therefore, nature-derived polymers can increase the bioactivity of synthetic polymers, when combined with them in nanofibrous scaffolds. Conversely, synthetic polymers can improve the electrospinnability and mechanical properties of the natural polymers. Similarly as synthetic polymers, nature-derived polymers can be more or less degradable in human tissues. Degradable polymers include collagen, gelatin, elastin, keratin, glycosaminoglycans, but also chitosan, gellan gum and PHBV, that is, polymers produced by other than mammalian organisms. Polymers produced by other organisms, such as bacteria, fungi, algae, plants or insects, are usually nondegradable in human tissues, or their degradability is limited due to lack of appropriate enzymes. These polymers include glucans, such as cellulose or dextran, and other polysaccharides and proteins, such as pullulan, alginate, pectin, and silk fibroin. Well-degradable polymers are recommended as direct scaffolds for tissue engineering, while less-degradable polymers are suitable for “intelligent” wound dressing for drug delivery and cell delivery.
\n
\n
Acknowledgments
\n
This review article was supported by the Grant Agency of the Czech Republic (grants No. 17-02448S and 17-00885S).
\n
\n',keywords:"skin replacements, wound dressings, nanofibers, electrospinning, epidermis, dermis, keratinocytes, fibroblasts, stem cells, vascularization, cell delivery, drug delivery, regenerative medicine",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/68698.pdf",chapterXML:"https://mts.intechopen.com/source/xml/68698.xml",downloadPdfUrl:"/chapter/pdf-download/68698",previewPdfUrl:"/chapter/pdf-preview/68698",totalDownloads:604,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 5th 2019",dateReviewed:"July 15th 2019",datePrePublished:"August 21st 2019",datePublished:"May 6th 2020",dateFinished:"August 21st 2019",readingETA:"0",abstract:"Nanofibrous scaffolds belong to the most suitable materials for tissue engineering, because they mimic the fibrous component of the natural extracellular matrix. This chapter is focused on the application of nanofibers in skin tissue engineering and wound healing, because the skin is the largest and vitally important organ in the human body. Nanofibrous meshes can serve as substrates for adhesion, growth and differentiation of skin and stem cells, and also as an antimicrobial and moisture-retaining barrier. These meshes have been prepared from a wide range of synthetic and nature-derived polymers. This chapter is focused on the use of nature-derived polymers. These polymers have good or limited degradability in the human tissues, which depends on their origin and on the presence of appropriate enzymes in the human tissues. Non-degradable and less-degradable polymers are usually produced in bacteria, fungi, algae, plants or insects, and include, for example, cellulose, dextran, pullulan, alginate, pectin and silk fibroin. Well-degradable polymers are usually components of the extracellular matrix in the human body or at least in other vertebrates, and include collagen, elastin, keratin and hyaluronic acid, although some polymers produced by non-vertebrate organisms, such as chitosan or poly(3-hydroxybutyrate-co-3-hydroxyvalerate), are also degradable in the human body.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/68698",risUrl:"/chapter/ris/68698",signatures:"Lucie Bacakova, Julia Pajorova, Marketa Zikmundova, Elena Filova, Petr Mikes, Vera Jencova, Eva Kuzelova Kostakova and Alla Sinica",book:{id:"9048",title:"Current and Future Aspects of Nanomedicine",subtitle:null,fullTitle:"Current and Future Aspects of Nanomedicine",slug:"current-and-future-aspects-of-nanomedicine",publishedDate:"May 6th 2020",bookSignature:"Islam Ahmed Hamed Khalil",coverURL:"https://cdn.intechopen.com/books/images_new/9048.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-870-9",printIsbn:"978-1-78985-869-3",pdfIsbn:"978-1-78984-438-2",editors:[{id:"226598",title:"Dr.",name:"Islam",middleName:null,surname:"Khalil",slug:"islam-khalil",fullName:"Islam Khalil"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"179175",title:"Dr.",name:"Lucie",middleName:null,surname:"Bacakova",fullName:"Lucie Bacakova",slug:"lucie-bacakova",email:"lucie.bacakova@fgu.cas.cz",position:null,institution:{name:"Palacký University, Olomouc",institutionURL:null,country:{name:"Czech Republic"}}},{id:"188643",title:"MSc.",name:"Julia",middleName:null,surname:"Pajorova",fullName:"Julia Pajorova",slug:"julia-pajorova",email:"Julia.Pajorova@fgu.cas.cz",position:null,institution:null},{id:"246891",title:"Dr.",name:"Elena",middleName:null,surname:"Filova",fullName:"Elena Filova",slug:"elena-filova",email:"Elena.Filova@fgu.cas.cz",position:null,institution:null},{id:"309511",title:"Dr.",name:"Marketa",middleName:null,surname:"Zikmundova",fullName:"Marketa Zikmundova",slug:"marketa-zikmundova",email:"Marketa.Zikmundova@fgu.cas.cz",position:null,institution:null},{id:"309513",title:"Dr.",name:"Petr",middleName:null,surname:"Mikes",fullName:"Petr Mikes",slug:"petr-mikes",email:"petr.mikes@tul.cz",position:null,institution:{name:"Technical University of Liberec",institutionURL:null,country:{name:"Czech Republic"}}},{id:"309514",title:"Dr.",name:"Vera",middleName:null,surname:"Jencova",fullName:"Vera Jencova",slug:"vera-jencova",email:"vera.jencova@tul.cz",position:null,institution:null},{id:"309515",title:"Dr.",name:"Eva",middleName:null,surname:"Kuzelova Kostakova",fullName:"Eva Kuzelova Kostakova",slug:"eva-kuzelova-kostakova",email:"Eva.Kostakova@seznam.cz",position:null,institution:null},{id:"309516",title:"Dr.",name:"Alla",middleName:null,surname:"Sinica",fullName:"Alla Sinica",slug:"alla-sinica",email:"Alla.Sinica@vscht.cz",position:null,institution:null}],sections:[{id:"sec_1",title:"1. 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Biomacromolecules. 2018;19(2):490-498. DOI: 10.1021/acs.biomac.7b01605\n'},{id:"B57",body:'\nSaruchi, Kaith BS, Jindal R, Kumar V. Biodegradation of gum tragacanth acrylic acid based hydrogel and its impact on soil fertility. Polymer Degradation and Stability. 2015;115:24-31. DOI: 10.1016/j.polymdegradstab. 2015.02.009\n'},{id:"B58",body:'\nHindi SSZ, Albureikan MO, Al-Ghamdi AA, Alhummiany H, Ansari MS. Synthesis, characterization and biodegradation of gum arabic-based bioplastic membranes. Nanoscience and Nanotechnology Research. 2017;4(2):32-42. DOI: 10.12691/nnr-4-2-1\n'},{id:"B59",body:'\nZarekhalili Z, Bahrami SH, Ranjbar-Mohammadi M, Milan PB. Fabrication and characterization of PVA/gum tragacanth/PCL hybrid nanofibrous scaffolds for skin substitutes. International Journal of Biological Macromolecules. 2017;94(Pt A):679-690. DOI: 10.1016/j.ijbiomac.2016.10.042\n'},{id:"B60",body:'\nRanjbar-Mohammadi M, Rabbani S, Bahrami SH, Joghataei MT, Moayer F. Antibacterial performance and in vivo diabetic wound healing of curcumin loaded gum tragacanth/poly(ε-caprolactone) electrospun nanofibers. Materials Science & Engineering. C, Materials for Biological Applications. 2016;69:1183-1191. DOI: 10.1016/j.msec.2016.08.032\n'},{id:"B61",body:'\nPedram Rad Z, Mokhtari J, Abbasi M. Calendula officinalis extract/PCL/Zein/gum arabic nanofibrous bio-composite scaffolds via suspension, two-nozzle and multilayer electrospinning for skin tissue engineering. International Journal of Biological Macromolecules. 2019;135:530-543. DOI: 10.1016/j.ijbiomac.2019.05.204\n'},{id:"B62",body:'\nSrivastava CM, Purwar R. Fabrication of robust Antheraea assama fibroin nanofibrous mat using ionic liquid for skin tissue engineering. Materials Science & Engineering. C, Materials for Biological Applications. 2016;68:276-290. DOI: 10.1016/j.msec.2016.05.020\n'},{id:"B63",body:'\nSrivastava CM, Purwar R, Gupta AP. Enhanced potential of biomimetic, silver nanoparticles functionalized Antheraea mylitta (tasar) silk fibroin nanofibrous mats for skin tissue engineering. International Journal of Biological Macromolecules. 2019;130:437-453. DOI: 10.1016/j.ijbiomac.2018.12.255\n'},{id:"B64",body:'\nChouhan D, Chakraborty B, Nandi SK, Mandal BB. Role of non-mulberry silk fibroin in deposition and regulation of extracellular matrix towards accelerated wound healing. Acta Biomaterialia. 2017;48:157-174. DOI: 10.1016/j.actbio.2016.10.019\n'},{id:"B65",body:'\nCao Y, Wang B. Biodegradation of silk biomaterials. International Journal of Molecular Sciences. 2009;10(4):1514-1524. DOI: 10.3390/ijms10041514\n'},{id:"B66",body:'\nWang Y, Rudym DD, Walsh A, Abrahamsen L, Kim HJ, Kim HS, et al. In vivo degradation of three-dimensional silk fibroin scaffolds. Biomaterials. 2008;29(24-25):3415-3428. 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Biomacromolecules. 2008;9(4):1106-1116. DOI: 10.1021/bm700875a\n'},{id:"B74",body:'\nShan YH, Peng LH, Liu X, Chen X, Xiong J, Gao JQ. Silk fibroin/gelatin electrospun nanofibrous dressing functionalized with astragaloside IV induces healing and anti-scar effects on burn wound. International Journal of Pharmaceutics. 2015;479(2):291-301. DOI: 10.1016/j.ijpharm.2014.12.067\n'},{id:"B75",body:'\nLi L, Qian Y, Jiang C, Lv Y, Liu W, Zhong L, et al. The use of hyaluronan to regulate protein adsorption and cell infiltration in nanofibrous scaffolds. Biomaterials. 2012;33(12):3428-3445. DOI: 10.1016/j.biomaterials.2012.01.038\n'},{id:"B76",body:'\nSheng X, Fan L, He C, Zhang K, Mo X, Wang H. Vitamin E-loaded silk fibroin nanofibrous mats fabricated by green process for skin care application. International Journal of Biological Macromolecules. 2013;56:49-56. DOI: 10.1016/j.ijbiomac.2013.01.029\n'},{id:"B77",body:'\nFan L, Cai Z, Zhang K, Han F, Li J, He C, et al. Green electrospun pantothenic acid/silk fibroin composite nanofibers: Fabrication, characterization and biological activity. Colloids and Surfaces. B, Biointerfaces. 2014;117:14-20. DOI: 10.1016/j.colsurfb.2013.12.030\n'},{id:"B78",body:'\nLin S, Chen M, Jiang H, Fan L, Sun B, Yu F, et al. Green electrospun grape seed extract-loaded silk fibroin nanofibrous mats with excellent cytocompatibility and antioxidant effect. Colloids and Surfaces. B, Biointerfaces. 2016;139:156-163. DOI: 10.1016/j.colsurfb.2015.12.001\n'},{id:"B79",body:'\nKandhasamy S, Arthi N, Arun RP, Verma RS. Synthesis and fabrication of novel quinone-based chromenopyrazole antioxidant-laden silk fibroin nanofibers scaffold for tissue engineering applications. Materials Science & Engineering. C, Materials for Biological Applications. 2019;102:773-787. DOI: 10.1016/j.msec.2019.04.076\n'},{id:"B80",body:'\nSuganya S, Venugopal J, Ramakrishna S, Lakshmi BS, Dev VR. 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Antimicrobial quaternary ammonium organosilane cross-linked nanofibrous collagen scaffolds for tissue engineering. International Journal of Nanomedicine. 2018;13:4473-4492. DOI: 10.2147/IJN.S159770\n'},{id:"B98",body:'\nRavichandran R, Venugopal JR, Sundarrajan S, Mukherjee S, Sridhar R, Ramakrishna S. Composite poly-L-lactic acid/poly-(α,β)-DL-aspartic acid/collagen nanofibrous scaffolds for dermal tissue regeneration. Materials Science & Engineering. C, Materials for Biological Applications. 2012;32(6):1443-1451. DOI: 10.1016/j.msec.2012.04.024\n'},{id:"B99",body:'\nAlamein MA, Stephens S, Liu Q , Skabo S, Warnke PH. Mass production of nanofibrous extracellular matrix with controlled 3D morphology for large-scale soft tissue regeneration. Tissue Engineering. Part C, Methods. 2013;19(6):458-472. DOI: 10.1089/ten.TEC.2012.0417\n'},{id:"B100",body:'\nPeh P, Lim NS, Blocki A, Chee SM, Park HC, Liao S, et al. Simultaneous delivery of highly diverse bioactive compounds from blend electrospun fibers for skin wound healing. Bioconjugate Chemistry. 2015;26(7):1348-1358. DOI: 10.1021/acs.bioconjchem.5b00123\n'},{id:"B101",body:'\nGümüşderelioğlu M, Dalkıranoğlu S, Aydın RS, Cakmak S. A novel dermal substitute based on biofunctionalized electrospun PCL nanofibrous matrix. Journal of Biomedical Materials Research. Part A. 2011;98(3):461-472. DOI: 10.1002/jbm.a.33143\n'},{id:"B102",body:'\nAlbright V, Xu M, Palanisamy A, Cheng J, Stack M, Zhang B, et al. Micelle-coated, hierarchically structured nanofibers with dual-release capability for accelerated wound healing and infection control. Advanced Healthcare Materials. 2018;7(11):e1800132. DOI: 10.1002/adhm.201800132\n'},{id:"B103",body:'\nAbdul Khodir WKW, Abdul Razak AH, Ng MH, Guarino V, Susanti D. Encapsulation and characterization of gentamicin sulfate in the collagen added electrospun nanofibers for skin regeneration. J Funct Biomater. 2018;9(2):E36. DOI: 10.3390/jfb9020036\n'},{id:"B104",body:'\nWang C, Wang Q , Gao W, Zhang Z, Lou Y, Jin H, et al. Highly efficient local delivery of endothelial progenitor cells significantly potentiates angiogenesis and full-thickness wound healing. Acta Biomaterialia. 2018;69:156-169. DOI: 10.1016/j.actbio.2018.01.019\n'},{id:"B105",body:'\nGhosal K, Manakhov A, Zajíčková L, Thomas S. Structural and surface compatibility study of modified electrospun poly(ε-caprolactone) (PCL) composites for skin tissue engineering. AAPS PharmSciTech. 2017;18(1):72-81. DOI: 10.1208/s12249-016-0500-8\n'},{id:"B106",body:'\nXie X, Li D, Su C, Cong W, Mo X, Hou G, et al. Functionalized biomimetic composite nanfibrous scaffolds with antibacterial and hemostatic efficacy for facilitating wound healing. Journal of Biomedical Nanotechnology. 2019;15(6):1267-1279. DOI: 10.1166/jbn.2019.2756\n'},{id:"B107",body:'\nYao CH, Chen KY, Chen YS, Li SJ, Huang CH. Lithospermi radix extract-containing bilayer nanofiber scaffold for promoting wound healing in a rat model. Materials Science & Engineering. C, Materials for Biological Applications. 2019;96:850-858. DOI: 10.1016/j.msec.2018.11.053\n'},{id:"B108",body:'\nAldana AA, Abraham GA. Current advances in electrospun gelatin-based scaffolds for tissue engineering applications. International Journal of Pharmaceutics. 2017;523(2):441-453. DOI: 10.1016/j.ijpharm.2016.09.044\n'},{id:"B109",body:'\nYao CH, Lee CY, Huang CH, Chen YS, Chen KY. Novel bilayer wound dressing based on electrospun gelatin/keratin nanofibrous mats for skin wound repair. Materials Science & Engineering. C, Materials for Biological Applications. 2017;79:533-540. DOI: 10.1016/j.msec.2017.05.076\n'},{id:"B110",body:'\nAdeli-Sardou M, Yaghoobi MM, Torkzadeh-Mahani M, Dodel M. Controlled release of lawsone from polycaprolactone/gelatin electrospun nano fibers for skin tissue regeneration. 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Cell infiltrative hydrogel fibrous scaffolds for accelerated wound healing. Acta Biomaterialia. 2017;49:66-77. DOI: 10.1016/j.actbio.2016.11.017\n'},{id:"B118",body:'\nDeFrates KG, Moore R, Borgesi J, Lin G, Mulderig T, Beachley V, et al. Protein-based fiber materials in medicine: A review. Nanomaterials. 2018;8(7). pii: E457. DOI: 10.3390/nano8070457\n'},{id:"B119",body:'\nKhalili S, Khorasani SN, Razavi SM, Hashemibeni B, Tamayol A. Nanofibrous scaffolds with biomimetic composition for skin regeneration. Applied Biochemistry and Biotechnology. 2019;187(4):1193-1203. DOI: 10.1007/s12010-018-2871-7\n'},{id:"B120",body:'\nRiedel T, Brynda E, Dyr JE, Houska M. Controlled preparation of thin fibrin films immobilized at solid surfaces. Journal of Biomedical Materials Research. Part A. 2009;88(2):437-447. DOI: 10.1002/jbm.a.31755\n'},{id:"B121",body:'\nLaw JX, Musa F, Ruszymah BH, El Haj AJ, Yang Y. A comparative study of skin cell activities in collagen and fibrin constructs. 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Fabrication and characterization of core-shell electrospun fibrous mats containing medicinal herbs for wound healing and skin tissue engineering. Marine Drugs. 2019;17(1). pii: E27. DOI: 10.3390/md17010027\n'},{id:"B129",body:'\nYan S, Zhang Q , Wang J, Liu Y, Lu S, Li M, et al. Silk fibroin/chondroitin sulfate/hyaluronic acid ternary scaffolds for dermal tissue reconstruction. Acta Biomaterialia. 2013;9(6):6771-6782. DOI: 10.1016/j.actbio.2013.02.016\n'},{id:"B130",body:'\nLi J, He A, Han CC, Fang D, Hsiao BS, Chu B. Electrospinning of hyaluronic acid (HA) and HA/gelatin blends. Macromolecular Rapid Communications. 2006;27:114-120. DOI: 10.1002/marc.200500726\n'},{id:"B131",body:'\nSéon-Lutz M, Couffin A-C, Vignoud S, Schlatter G, Hébraud A. Electrospinning in water and in situ crosslinking of hyaluronic acid / cyclodextrin nanofibers: Towards wound dressing with controlled drug release. Carbohydrate Polymers. 2019;207:276-287. DOI: 10.1016/j.carbpol.2018.11.085\n'},{id:"B132",body:'\nUm IC, Fang D, Hsiao BS, Okamoto A, Chu B. Electro-spinning and electro-blowing of hyaluronic acid. Biomacromolecules. 2004;5(4):1428-1436. DOI: 10.1021/bm034539b\n'},{id:"B133",body:'\nPokorny M, Rassushin V, Wolfova L, Velebny V. Increased production of nanofibrous materials by electroblowing from blends of hyaluronic acid and polyethylene oxide. Polymer Engineering and Science. 2016;56:932-938. DOI: 10.1002/pen.24322\n'},{id:"B134",body:'\nQian Y, Li L, Jiang C, Xu W, Lv Y, Zhong L, et al. The effect of hyaluronan on the motility of skin dermal fibroblasts in nanofibrous scaffolds. International Journal of Biological Macromolecules. 2015;79:133-143. DOI: 10.1016/j.ijbiomac.2015.04.059\n'},{id:"B135",body:'\nStodolak-Zych E, Rozmus K, Dzierzkowska E, Zych Ł, Rapacz-Kmita A, Gargas M, et al. The membrane with polylactide and hyaluronic fibers for skin substitute. Acta of Bioengineering and Biomechanics. 2018;20(4):91-99. DOI: 10.5277/ABB-01199-2018-02\n'},{id:"B136",body:'\nKurpinski KT, Stephenson JT, Janairo RR, Lee H, Li S. The effect of fiber alignment and heparin coating on cell infiltration into nanofibrous PLLA scaffolds. Biomaterials. 2010;31(13):3536-3542. DOI: 10.1016/j.biomaterials.2010.01.062\n'},{id:"B137",body:'\nYergoz F, Hastar N, Cimenci CE, Ozkan AD, Tekinay T, Guler MO, et al. Heparin mimetic peptide nanofiber gel promotes regeneration of full thickness burn injury. Biomaterials. 2017;134:117-127. DOI: 10.1016/j.biomaterials.2017.04.040\n'},{id:"B138",body:'\nSadeghi A, Zandi M, Pezeshki-Modaress M, Rajabi S. Tough, hybrid chondroitin sulfate nanofibers as a promising scaffold for skin tissue engineering. International Journal of Biological Macromolecules. 2019;132:63-75. DOI: 10.1016/j.ijbiomac.2019.03.208. 27\n'},{id:"B139",body:'\nPezeshki-Modaress M, Mirzadeh H, Zandi M, Rajabi-Zeleti S, Sodeifi N, Aghdami N, et al. Gelatin/chondroitin sulfate nanofibrous scaffolds for stimulation of wound healing: In-vitro and in-vivo study. Journal of Biomedical Materials Research. Part A. 2017;105(7):2020-2034. DOI: 10.1002/jbm.a.35890\n'},{id:"B140",body:'\nAzuma K, Ifuku S, Osaki T, Okamoto Y, Minami S. Preparation and biomedical applications of chitin and chitosan nanofibers. Journal of Biomedical Nanotechnology. 2014;10(10):2891-2920. DOI: 10.1166/jbn.2014.1882\n'},{id:"B141",body:'\nKai D, Liow SS, Loh XJ. Biodegradable polymers for electrospinning: towards biomedical applications. Materials Science and Engineering C: Materials for Biological Applications. 2014;45:659-670. DOI: 10.1016/j.msec.2014.04.051\n'},{id:"B142",body:'\nPal P, Dadhich P, Srivas PK, Das B, Maulik D, Dhara S. Bilayered nanofibrous 3D hierarchy as skin rudiment by emulsion electrospinning for burn wound management. Biomaterials Science. 2017;5(9):1786-1799. DOI: 10.1039/c7bm00174f\n'},{id:"B143",body:'\nGomes S, Rodrigues G, Martins G, Henriques C, Silva JC. Evaluation of nanofibrous scaffolds obtained from blends of chitosan, gelatin and polycaprolactone for skin tissue engineering. International Journal of Biological Macromolecules. 2017;102:1174-1185. DOI: 10.1016/j.ijbiomac.2017.05.004\n'},{id:"B144",body:'\nMahdavi M, Mahmoudi N, Rezaie Anaran F, Simchi A. Electrospinning of nanodiamond-modified polysaccharide nanofibers with physico-mechanical properties close to natural skins. Marine Drugs. 2016;14(7). pii: E128. DOI: 10.3390/md14070128\n'},{id:"B145",body:'\nVeleirinho B, Coelho DS, Dias PF, Maraschin M, Ribeiro-do-Valle RM, Lopes-da-Silva JA. Nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/chitosan scaffolds for skin regeneration. International Journal of Biological Macromolecules. 2012;51(4):343-350. DOI: 10.1016/j.ijbiomac.2012.05.023\n'},{id:"B146",body:'\nShalumon KT, Sathish D, Nair SV, Chennazhi KP, Tamura H, Jayakumar R. Fabrication of aligned poly(lactic acid)-chitosan nanofibers by novel parallel blade collector method for skin tissue engineering. Journal of Biomedical Nanotechnology. 2012;8(3):405-416. DOI: 10.1166/jbn.2012.1395\n'},{id:"B147",body:'\nMo Y, Guo R, Zhang Y, Xue W, Cheng B, Zhang Y. Controlled dual delivery of angiogenin and curcumin by electrospun nanofibers for skin regeneration. Tissue Engineering. Part A. 2017;23(13-14):597-608. DOI: 10.1089/ten.tea.2016.0268\n'},{id:"B148",body:'\nMengistu Lemma S, Bossard F, Rinaudo M. Preparation of pure and stable chitosan nanofibers by electrospinning in the presence of poly(ethylene oxide). International Journal of Molecular Sciences. 2016;17(11):E1790. DOI: 10.3390/ijms17111790\n'},{id:"B149",body:'\nKoosha M, Raoufi M, Moravvej H. One-pot reactive electrospinning of chitosan/PVA hydrogel nanofibers reinforced by halloysite nanotubes with enhanced fibroblast cell attachment for skin tissue regeneration. Colloids and Surfaces. B, Biointerfaces. 2019;179:270-279. DOI: 10.1016/j.colsurfb.2019.03.054\n'},{id:"B150",body:'\nMahmoudi N, Eslahi N, Mehdipour A, Mohammadi M, Akbari M, Samadikuchaksaraei A, et al. Temporary skin grafts based on hybrid graphene oxide-natural biopolymer nanofibers as effective wound healing substitutes: Pre-clinical and pathological studies in animal models. Journal of Materials Science. Materials in Medicine. 2017;28(5):73. DOI: 10.1007/s10856-017-5874-y\n'},{id:"B151",body:'\nYousefi I, Pakravan M, Rahimi H, Bahador A, Farshadzadeh Z, Haririan I. An investigation of electrospun henna leaves extract-loaded chitosan based nanofibrous mats for skin tissue engineering. Materials Science & Engineering. C, Materials for Biological Applications. 2017;75:433-444. DOI: 10.1016/j.msec.2017.02.076\n'},{id:"B152",body:'\nPiran M, Vakilian S, Piran M, Mohammadi-Sangcheshmeh A, Hosseinzadeh S, Ardeshirylajimi A. In vitro fibroblast migration by sustained release of PDGF-BB loaded in chitosan nanoparticles incorporated in electrospun nanofibers for wound dressing applications. Artif Cells Nanomed Biotechnol. 2018;46(supp 1):511-520. DOI: 10.1080/21691401.2018.1430698\n'},{id:"B153",body:'\nTanha S, Rafiee-Tehrani M, Abdollahi M, Vakilian S, Esmaili Z, Naraghi ZS, et al. G-CSF loaded nanofiber/nanoparticle composite coated with collagen promotes wound healing in vivo. Journal of Biomedical Materials Research. Part A. 2017;105(10):2830-2842. DOI: 10.1002/jbm.a.36135\n'},{id:"B154",body:'\nNoh HK, Lee SW, Kim JM, Oh JE, Kim KH, Chung CP, et al. Electrospinning of chitin nanofibers: Degradation behavior and cellular response to normal human keratinocytes and fibroblasts. Biomaterials. 2006;27(21):3934-3944. DOI: 10.1016/j.biomaterials.2006.03.016\n'},{id:"B155",body:'\nVashisth P, Pruthi V. Synthesis and characterization of crosslinked gellan/PVA nanofibers for tissue engineering application. Materials Science & Engineering. C, Materials for Biological Applications. 2016;67:304-312. DOI: 10.1016/j.msec.2016.05.049\n'},{id:"B156",body:'\nVashisth P, Nikhil K, Roy P, Pruthi PA, Singh RP, Pruthi V. A novel gellan-PVA nanofibrous scaffold for skin tissue regeneration: Fabrication and characterization. Carbohydrate Polymers. 2016;136:851-859. DOI: 10.1016/j.carbpol.2015.09.113\n'},{id:"B157",body:'\nVashisth P, Srivastava AK, Nagar H, Raghuwanshi N, Sharan S, Nikhil K, et al. Drug functionalized microbial polysaccharide based nanofibers as transdermal substitute. Nanomedicine. 2016;12(5):1375-1385. DOI: 10.1016/j.nano.2016.01.019\n'},{id:"B158",body:'\nBonifacio MA, Cometa S, Cochis A, Gentile P, Ferreira AM, Azzimonti B, et al. Data on Manuka Honey/Gellan gum composite hydrogels for cartilage repair. Data in Brief. 2018;20:831-839. DOI: 10.1016/j.dib.2018.08.155\n'},{id:"B159",body:'\nYu I, Kaonis S, Roland CR. A study on degradation behavior of 3D printed gellan gum scaffolds. Procedia CIRP. 2017;65:78-83. DOI: 10.1016/j.procir.2017.04.020\n'},{id:"B160",body:'\nLin T, Lu C, Zhu L, Lu T. The biodegradation of zein in vitro and in vivo and its application in implants. AAPS PharmSciTech. 2011;12(1):172-176. DOI: 10.1208/s12249-010-9565-y\n'},{id:"B161",body:'\nMaharjan B, Joshi MK, Tiwari AP, Park CH, Kim CS. In-situ synthesis of AgNPs in the natural/synthetic hybrid nanofibrous scaffolds: Fabrication, characterization and antimicrobial activities. Journal of the Mechanical Behavior of Biomedical Materials. 2017;65:66-76. DOI: 10.1016/j.jmbbm.2016.07.034\n'},{id:"B162",body:'\nZhang M, Li X, Li S, Liu Y, Hao L. Electrospun poly(l-lactide)/zein nanofiber mats loaded with Rana chensinensis skin peptides for wound dressing. Journal of Materials Science. Materials in Medicine. 2016;27(9):136. DOI: 10.1007/s10856-016-5749-7\n'},{id:"B163",body:'\nFigueira DR, Miguel SP, de Sá KD, Correia IJ. Production and characterization of polycaprolactone- hyaluronic acid/chitosan- zein electrospun bilayer nanofibrous membrane for tissue regeneration. International Journal of Biological Macromolecules. 2016;93(Pt A):1100-1110. DOI: 10.1016/j.ijbiomac.2016.09.080\n'},{id:"B164",body:'\nBabitha S, Korrapati PS. Biodegradable zein-polydopamine polymeric scaffold impregnated with TiO2 nanoparticles for skin tissue engineering. Biomedical Materials. 2017;12(5):055008. DOI: 10.1088/1748-605X/aa7d5a\n'},{id:"B165",body:'\nSultana N, Khan TH. In vitro degradation of PHBV scaffolds and nHA/PHBV composite scaffolds containing hydroxyapatite nanoparticles for bone tissue engineering. Journal of Nanomaterials. 2012;2012:190950. DOI: 10.1155/2012/190950\n'},{id:"B166",body:'\nSundaramurthi D, Krishnan UM, Sethuraman S. Epidermal differentiation of stem cells on poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanofibers. Annals of Biomedical Engineering. 2014;42(12):2589-2599. DOI: 10.1007/s10439-014-1124-3\n'},{id:"B167",body:'\nKeshel SH, Biazar E, Rezaei Tavirani M, Rahmati Roodsari M, Ronaghi A, Ebrahimi M, et al. The healing effect of unrestricted somatic stem cells loaded in collagen-modified nanofibrous PHBV scaffold on full-thickness skin defects. Artif Cells Nanomed Biotechnol. 2014;42(3):210-216. DOI: 10.3109/21691401.2013.800080\n'},{id:"B168",body:'\nZine R, Sinha M. Nanofibrous poly(3-hydroxybutyrate-co-3-hydroxyvalerate)/collagen/graphene oxide scaffolds for wound coverage. Materials Science & Engineering. C, Materials for Biological Applications. 2017;80:129-134. DOI: 10.1016/j.msec.2017.05.138\n'},{id:"B169",body:'\nYuan J, Geng J, Xing Z, Shim KJ, Han I, Kim J, et al. Novel wound dressing based on nanofibrous PHBV-keratin mats. Journal of Tissue Engineering and Regenerative Medicine. 2015;9(9):1027-1035. DOI: 10.1002/term.1653\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Lucie Bacakova",address:"lucie.bacakova@fgu.cas.cz",affiliation:'
Department of Biomaterials and Tissue Engineering, Institute of Physiology of the Czech Academy of Sciences, Czech Republic
BIOCEV, 1st Faculty of Medicine, Charles University, Czech Republic
Department of Analytical Chemistry, University of Chemistry and Technology Prague, Czech Republic
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Thesis 'Mechanical-Mathematical Modelling of the Lithosphere Geodynamics”.\r\n Leading Scientist, Head of International Projects Department of Sergeev Institute of Environmental Geoscience, Russian Academy of Sciences. \r\n\r\nScientific research fields:\r\nMechanical-mathematical modelling in geology, geothermal investigations, computer modelling, geothermal energy use, paleoclimate changes and reconstruction, sustainable development, environmental problems decision, natural hazards, landslides, risk analysis.\r\nMore than 400 scientific publications.\r\nResults of research were presented at more than 100 International Scientific Conferences and Congresses in more than 50 countries.\r\n\r\nMember of International and Scientific Organizations:\r\n International Geothermal Association (IGA).\r\nIGA Board of Directors . \r\nPresident of Geothermal Energy Society (GES) of Russia.\r\nAssociate Member of the International Informatization Academy.\r\nIAMG (International Association for Mathematical Geosciences).\r\nScientific Secretary of Geothermal Council of Russia, Russian Academy of Sciences. \r\nICL (International Consortium on Landslides). \r\nICL BoR (International Consortium on Landslides, Board of Representatives).\r\nInternational Best Paper Award 'PRESSZVANIE”, nomination 'Clean Energy”, 2015.",institutionString:"Sergeev Institute of Environment Geoscience, Russian Academy of Sciences",institution:{name:"Sergeev Institute of Environmental Geoscience",institutionURL:null,country:{name:"Russia"}}}]},generic:{page:{slug:"authorship-policy",title:"Authorship Policy",intro:'
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AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
Substantially contribute to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work
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Participate in drafting or revising the work
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Approve the final version of the work to be published.
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All contributors who meet these criteria are listed as Authors. Their exact contributions should be described in the manuscript at the time of submission.
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CHANGES IN AUTHORSHIP
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If it is felt necessary to make changes to the list of Authors after a manuscript has been submitted or published, it is the responsibility of the Author concerned to provide a valid reason to amend the published list. Additionally, all listed Authors must verify and approve the proposed changes in order for any amendments to be made.
\n\n
AFFILIATION
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Authors are responsible for ensuring all addresses and emails provided are correct. Under affiliation(s) all Authors should indicate where the research was conducted. Please note that no changes to the affiliation(s) can be made after the chapter has been published.
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Policy last updated: 2017-05-29
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