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1. Introduction
Epidermolysis bullosa (EB) refers to a group of rare genodermatoses typically characterized by vulnerability of the skin to friction or trauma, leading to blistering and wounding to various extents, i.e. from localized and mild to generalized and severe, depending on the respective subtype of the disease. EB subtypes are classified according to the mutated gene, the resulting product of which is either functionally impaired or absent, and the level at which tissue cleavage occurs. While involvement in some subtypes are restricted to the skin, for others, extracutaneous organs (i.e. mucosa and eyes) may be involved, along with a multitude of secondary manifestations that significantly impair patients’ life quality (QoL) and may even be life-threatening. Among these is the development of an aggressive form of cutaneous squamous cell carcinoma (cSCC) in patients with the severe dystrophic subtype of the disease [1, 2, 3].
Worldwide approximately 500,000 people suffer from EB, which can be classified into four major groups [1]. Mainly dominantly inherited mutations within genes encoding keratin 5, 14 and plectin lead to EB simplex (EBS), associated with intraepidermal blister formation (Figure 1). Mutations within genes, encoding laminin-332, type XVII collagen or integrin-α6β4, are the main causes of the junctional form of EB (JEB), characterized by tissue separation within the lamina lucida of the basement membrane zone (BMZ). The severe dystrophic variant of EB (DEB) is caused exclusively by mutations within the gene COL7A1, encoding type VII collagen, resulting in tissue separation within the sub-lamina densa (Figure 1). Kindler syndrome is caused by recessive mutations within the KIND1 gene leading to a complete loss of encoded Kindlin-1 and blistering in multiple skin layers [1].
Figure 1.
Therapeutic targets in EB and strategies in development against them. EB is a rare hereditary skin fragility disorder characterized by blistering and wounding. In severe subtypes of the disease, wounds degenerate into tumors. The different therapeutic strategies to target important aspects of the disease are depicted.
Despite advances in our understanding of the spectrum of pathologies associated with the different subtypes of EB, a systemic cure is still out of reach. However, the increasing number of trials that are being conducted reflects significant progress in clinical research, including strategies to correct and/or modulate the aberrant molecules and mechanisms underlying this devastating disease. [4, 5, 6, 7] The remarkable differences between EB-types and numerous subtypes, renders the development of therapies a complex challenge, as both inter-subtype and inter-individual differences require the development of more personalized treatments.
Major complications in EB range from itch and pain, to a predisposition to wound chronification and tumor development, with molecular contributors deriving from various sources including different tissue-associated cell types, matrix components, as well as inflammatory events. The majority of these comorbidities, in and of themselves, are not unique to EB, so that the repurposing of clinically approved treatments against such symptoms represents an attractive path for a more rapid market approval of these compounds for EB. Furthermore, new evidence arising in the study of these common conditions can be leveraged to direct therapy development in EB. Nevertheless, rigorous evaluation for safety in this specific, vulnerable patient group is warranted for any candidate therapeutic. This is especially true for cancer therapies which are associated with significant cellular toxicity and often have the adverse effect of exacerbating the wound healing deficiencies associated with the disease.
2. Therapy development for EB
2.1 Causal therapies for epidermolysis bullosa
2.1.1 Gene replacement therapies for epidermolysis bullosa
The development of causal therapies has always been a main focus of EB research (Table 1).
Overview on causal therapies in epidermolysis bullosa and their current clinical status.
Currently, gene replacement strategies that exploit viral vectors to introduce full-length wild type cDNA copies of the affected gene into the skin cells of patients [14], have advanced the furthest in clinical trials. However, this strategy relies on genomic integration of the transgene to achieve long-term restoration of gene function, which bears a low risk of genomic toxicity due to insertional mutagenesis that can result in tumor development as shown for for X-linked severe combined immunodeficiency (X-SCID) [44]. However, no such deleterious events have been observed thus far for EB [14, 15, 16, 17, 19]. In general, cutaneous gene therapies have the advantage that grafted skin areas are easy to monitor, with developing tumors easily detected and promptly excised. Until now, transplantation of genetically corrected skin grafts represents the most auspicious approach, due to the limited number of viral vectors suitable for in vivo targeting. Poor transcutaneous delivery of the vector and the size of the transgene represent further limitations [45, 46].
To date, the most successful application of gene replacement therapy has been achieved in junctional EB (JEB) patients carrying mutations in the LAMB3 gene [14, 16, 17]. In all three cases, epidermal stem cells isolated from skin biopsies and expanded in vitro, were treated with a Moloney leukemia virus (MLV)-derived retroviral vector expressing the full-length cDNA of LAMB3. Treated cells were then expanded into epidermal sheets, which were transplanted back onto the patient. To this day, the first patient treated in 2006 still retains the transgenic epidermis, which at 6.5 years follow-up, appeared normal, blister-free, and showed accurate localized expression of laminin-332 within the skin, and no adverse effects reported thus far [15]. More recently, the same procedure was applied to treat an eight-year old JEB patient with life-threatening skin loss due to a bacterial infection. Over the course of successive treatments, up to ~80% of the patient’s skin was surgically replaced by genetically corrected skin, demonstrating the life-saving potential of this therapeutic strategy for genodermatoses. Genetic analyses of the skin grafts clearly demonstrated that the transgenic epidermis was sustained by a defined number of epidermal stem cells with long-term regenerative potential [17].
Despite these successes, attempts to apply the same strategy in recessive dystrophic EB (RDEB) demonstrated no long-lasting effects. While long-term COL7A1 expression could be attained following treatment, variable clinical outcomes were observed, with persistent type VII collagen expression detected in only two out of seven treated patients at two years post transplantation. [19, 20]
For most patients, improved wound healing and an accurate deposition of type VII collagen within the regenerated skin could be detected. However, expression of the transgene significantly decreased over time [19]. Possible reasons for this include the size of the COL7A1 cDNA (~9 kb), the random nature of viral integrations, or post-transcriptional deregulation via aberrant splicing [21, 47]. In this respect, targeting LAMB3 via a gene replacement therapy bears a big advantage over COL7A1, as the phenotype of JEB is associated with a significant depletion of epidermal stem cells [48]. Here, the YAP/TAZ mechano-sensing pathway plays a major role in sustaining holoclones downstream of Laminin-332 signaling. Holoclones represent stem cells with the greatest reproductive capacity and are essential for epidermal regeneration. Thus laminin-332 gene therapy likely rescues YAP activity, enabling the maintenance of the pool of epidermal stem cells [48]. Thus, while these clinical trials in JEB and DEB demonstrate the potential of gene replacement-based therapies in EB, they also reveal the varying therapeutic efficiencies that can be expected among the different EB types, potentially depending on the biology of the respective matrix protein affected.
In contrast to targeting patient keratinocytes, a combined gene and cell therapy approach using patient autologous fibroblasts was recently evaluated in a phase I, open-label, single-center clinical trial in four RDEB patients [22]. Based on previous preclinical data [23], patient fibroblasts were first modified ex vivo to carry a full-length codon-optimized COL7A1 cDNA using a self-inactivating lentiviral vector. The gene-modified autologous fibroblasts were then injected intradermally back into the patients. The treatment was well-tolerated and no serious side effects were observed. Mean fluorescence intensity of type VII collagen staining in treated skin was 1.26-fold to 26.10-fold increased over non-injected skin, with enhanced expression sustained for up to 12 months in 2 out of the 4 patients [22]. This study demonstrated the potential of a combined gene & cell therapy approach for the treatment of RDEB, although more clinical data is required to evaluate the benefit for the patient.
2.1.2 Gene editing strategies for epidermolysis bullosa
Gene editing platforms based on programmable nucleases have advanced at a rapid pace, such that the correction of any gene is now, at least in theory, conceivable. At their core, designer nucleases consist of DNA endonucleases, such as zinc-finger nucleases (ZNF), transcription activator-like effector nucleases (TALEN) and clustered regularly interspaced short palindromic repeats (CRISPR) /CRISPR-associated protein 9 (Cas9), which are guided to specific DNA loci of interest, where they generate double-strand breaks (DSBs) and trigger the activation of DNA repair mechanisms [49, 50]. The most frequent repair pathway, termed non-homologous end joining pathway (NHEJ), relies on the introduction of small insertions and deletions (indels) at the DSB site [51], which can be leveraged for the inactivation of genes carrying dominant negative missense mutations [8, 52], or for the reframing of genes bearing pathogenic frameshift mutations [28, 29].
While not a genetic correction per se, gene disruption can be a suitable way of targeting dominant alleles via causing the coding sequence to run into a premature termination codon (PTC) during translation. Ribosomal stalling and activation of the nonsense-mediated mRNA decay pathway triggers the degradation of the edited mutant transcripts [53]. We have exploited this strategy to disrupt a dominant negative KRT5 mutation whilst leaving the wild type allele intact [8]. This targeting strategy should be applicable to a broad number of EBS patients. Similarly, for DDEB, Shinkuma et al. applied an allele-specific gene disruption approach to target a dominant negative mutation within COL7A1 [30].
The same strategy can also be used to reframe mutant mRNA and was recently shown by several groups to be a promising editing approach in RDEB [28, 29, 31, 32]. Leveraging recently developed algorithms to accurately predict end-joining (EJ) repair outcomes following CRISPR/Cas9-mediated cleavage, we were able to achieve significant restoration of COL7A1 function after targeting a pathogenic frameshift mutation within exon 73 of COL7A1 [29]. Sequence composition around the Cas9 binding site predicted a single adenine sense-strand insertion at the COL7A1 target locus as the dominant EJ repair outcome, which would restore the reading frame of the message while introducing a single amino acid change in the protein. Indeed, we detected this precise nucleotide modification in 17% of all next generation sequencing (NGS)-analyzed COL7A1 alleles, following a single RNP treatment. In all gene-edited cells analyzed, > 70% exhibited restored functional protein expression, underscoring the potential of end-joining based DNA repair strategies for restoring gene function in EB [29].
Of course, the holy grail of gene therapy has been to achieve a traceless repair of the disease-causing mutation. With current editing technologies, this is now attainable by invoking the high-fidelity homology directed repair (HDR) pathway. By providing an exogenous HDR donor sequence, which bears homology to the target region, the exchange of whole gene regions or individual nucleotides can be achieved [18, 24, 49, 50]. However, in comparison to EJ-based targeting strategies, gene editing efficiency is generally reduced, as homologous recombination is only active during the late S/G2 phase of the cell cycle [54]. Nevertheless, in EB, HDR-based gene repair strategies have been successfully applied to EBS [9] and RDEB cells [24, 33, 35] in vitro. The focus of therapy development currently lies on improving safety and efficiency, which are both prerequisites for any future in vivo application of this strategy. Towards this end, to circumvent the known off-target activity of wild type Streptococcus pyogenes Cas9 (SpCas9), we utilized a mutant Cas9D10A nuclease, which predominantly induces single-strand nicks instead of double-strand breaks within the DNA [55, 56]. Indeed, we found that targeting of mutant KRT14 or COL7A1 alleles with two guided nickases in a double-nicking configuration was safer and more efficient than the use of wild type spCas9 [9, 24]. Additional efficiency can be gained by optimizing both, the format and the delivery of the gene-editing molecules. Currently, electroporation of COL7A1-specific RNPs together with single-stranded oligonucleotide HDR templates have resulted in the highest repair efficiencies [34].
The application of HDR-based approaches to the correction of patient-derived induced pluripotent stem cells (iPSCs) further increases the range of therapeutic options for patients, especially as the isolation of epidermal holoclones can be a limiting factor [14, 34]. Pre-clinical studies using corrected iPSCs, that were then differentiated into keratinocytes and fibroblasts, and used to generate three-dimensional skin equivalents (HSEs) on the backs of immunodeficient mice, showed normal type VII collagen expression and restored anchoring fibrils [34]. Alternative strategies, not based on homology-directed repair, comprise base editing, which has proven to be a suitable option for correcting pathogenic mutations in RDEB [36]. The most recent genome editing tool, prime editing, can be used to directly write new genetic information into a selected genomic locus using a Cas9 nickase fused to an engineered reverse transcriptase (RT) domain [57]. Via a prime editing guide RNA (pegRNA), which specifies the target site and represents the RT template encoding the desired edit, the prime editor is directed to the target locus. Here, the Cas9 nickase makes a single strand DNA break, that induces the hybridization of the nicked genomic strand to the complementary primer binding site (PBS) sequence, located within the pegRNA. A subsequent reverse transcription of the RT template, carrying the desired edit, followed by a cellular DNA repair mechanism lead to the insertion of the respective genetic modification at the target site [57]. Prime editing potentially improves safety, efficiency and applicability, and its application to EB will undoubtedly be confirmed in appropriate disease models in the near future.
2.1.3 RNA-based therapies for epidermolysis bullosa
A promising RNA-based strategy for the restoration of functional protein expression in EB is based on the use of antisense oligonucleotides (AON) for the specific knockdown of genes or their modification via splicing interference [58]. AONs are generally short fragments of modified DNA or RNA which, in the case of splicing modulation, hybridize to splicing elements (e.g. splice acceptor site or enhancers) within an in-frame target exon during pre-mRNA splicing, thereby masking it from the splicing machinery and resulting in its exclusion from the mature transcript. Thus, a truncated protein carrying an in-frame deletion of one or more exons is translated from the new transcript. In the last decade, AON-mediated splicing modulation has been successfully applied in DEB keratinocytes to skip in-frame COL7A1 exon 70 [25], exon 73 [24, 26], exon 80 [26], and exon 105 [27] that carried dominant or recessive disease-causing mutations. The resulting proteins, though shorter, retained functionality. Indeed, COL7A1 is amenable to AON-based exon skipping strategies because of the numerous short in-frame exons that encode its collagenous domains [24]. Beyond proof-of-concept, formulation of an exon 73-specific AON, named QR-313, within a carbomer-composed gel for topical treatment of wounds in DEB, led to enhanced type VII collagen levels in human RDEB skin [24], and is currently being evaluated for safety and efficacy in clinical trials (NCT03605069). However, not all exons are suitable targets for exon skipping. Furthermore, amino acid sequences potentially vital for protein function may be deleted. Thus, AON-based gene repair approaches need to be carefully evaluated for each targeted gene, exon and even mutation, prior to their clinical application [27].
Another RNA-based strategy for mRNA correction, namely RNA trans-splicing (also termed spliceosome-mediated RNA trans-splicing, SMaRT), has emerged as an attractive therapeutic option for the correction of EB-associated mutations on the RNA level [10, 11, 12]. Here, the endogenous splicing machinery is exploited to selectively exchange mutation-bearing regions of the target pre-mRNA, with the corresponding wild type sequence from an exogenously provided RNA trans-splicing molecule (RTM) [59]. The engineered RTM contains a binding domain to direct its hybridization to the target pre-mRNA, as well as splicing elements required for efficient splicing, in addition to the wild-type coding sequence to be restored [59]. This approach has been applied to accurately restore gene function in a variety of human genetic diseases, including hemophilia A [60], muscular dystrophy [61, 62] or Alzheimer’s disease [63]. In EB, SMaRT-mediated RNA editing was first achieved for the PLEC gene [12], but has more recently, been used to correct the EB-associated genes KRT14 [10, 11, 13] and COL7A1 [37, 38, 39, 40] in vitro and in pre-clinical animal models. However, while these studies indicated a potential clinical applicability of SMaRT technology in gene therapy for EB, the efficiency of this RNA-based method needs to be significantly improved if it is to move forward towards clinical translation.
2.1.4 Protein- and cell-based therapies for epidermolysis bullosa
Protein replacement strategies were recently applied in preclinical studies for RDEB. The local or intravenous injection of recombinant type VII collagen led to its homing to the dermal-epidermal junction and promoted wound healing [41]. Another therapeutic option for RDEB is the administration of type VII collagen-expressing allogeneic fibroblasts into healing RDEB wounds. Particularly when injected intradermally allogeneic fibroblast therapy resulted in a significant decrease in wound area when compared to standard of care after 2 and 12 weeks of treatment [42].
2.1.5 Read-through strategies for epidermolysis bullosa
Premature stop codon (PTC) read-through strategies rely on agents that allow for the incorporation of a random amino acid at the PTC position in the mRNA. Depending on the importance of the original amino acid to protein function, as well as impact of the introduced amino acid to e.g. protein folding, stability, and post-translational processing, PTC read-through therapies can result in the synthesis of a functional full-length protein. This strategy has been shown to be feasible in RDEB-derived cells [64, 65]. Cogan et al. treated RDEB keratinocyte cell lines and RDEB fibroblasts carrying PTC mutations, with the aminoglycosides geneticin, gentamicin and paromomycin. Full-length type VII collagen was accurately synthesized and secreted in a dose-dependent and sustained manner, highlighting the therapeutic potential of PTC read-through approaches for RDEB patients [65]. This resulted in a clinical trial to assess safety and efficacy of topical and intradermal gentamicin treatment in 5 RDEB patients with nonsense mutations application led to induced type VII collagen expression and anchoring fibril generation at the dermal-epidermal junction of treated skin areas, with improved wound closure and reduced blistering [43]. However, the toxicity associated with long-term aminoglycoside use currently hinders their widespread clinical application for these purposes. Alternatively, the FDA-approved anti-inflammatory drug amlexanox has been demonstrated to induce full-length collagen type VII expression in vitro in 8 out of 12 different RDEB PTC alleles tested. Furthermore, read-through synthesis correlated with the phosphorylation of the RNA helicase UPF-1, suggesting that inhibition of nonsense mediated decay of the PTC-containing mRNA contributed to its mechanism of action [64]. However, increased read-through translation alone is insufficient to achieve proper function, and additionally accurate deposition of the protein at the basement membrane zone likely needs to be confirmed for each PTC mutation. Similar to the mentioned RDEB studies, the aminoglycoside gentamicin was recently applied to JEB keratinocytes carrying various nonsense mutations within the LAMB3 gene [66]. As a result, the authors achieved PTC read-through leading to the synthesis and secretion of the respective laminin chain protein as well as the restoration of laminin-332 assembly [66]. Nevertheless, future studies are required to address current issues concerning read-through-based approaches such as the toxicity and bioavailability of applied compounds and their interactions within treated cells and organisms.
In summary, numerous strategies to target the genetic cause of EB, as well as ameliorate disease-associated complications, are under intensive investigation. These act at various levels, from genes and gene products, to cellular pathways, tissue processes, and systemic events. While each strategy has distinct strengths and challenges, they all share the overarching aim of significatnly improving the QoL of patients (Figure 2).
Figure 2.
Causal therapy options for epidermolysis bullosa. Current strategies targeting the genetic cause of EB can be designed to act either on DNA level (cDNA replacement, gene editing), RNA level (AON-mediated exon skipping, SMaRT), RNA/protein level (PTC readthrough) or tissue level (protein replacement fibroblast/MSC therapy).
2.1.6 Immunological aspects of causal therapy
Immunological tolerance to self-antigens result from central and peripheral tolerance mechanisms. Central tolerance in the thymus results in either negative selection of self-reactive T cells or development of self-specific suppressive regulatory T cells, both of which require expression and presentation of self-antigens to developing thymocytes. Additionally, various peripheral mechanisms of tolerance protect the body from deleterious reactions against self-tissues. These include anatomical sequestration of self-antigens, deletion of peripheral autoreactive lymphocytes, the development of functional unresponsiveness of lymphocytes (anergy) and action of regulatory T cells [67, 68].
A major risk in patients, especially those completely lacking expression of the affected protein, is that this protein is missing from the repertoire of self-antigens presented during central tolerance establishment. As the aim of causal therapies is to restore the missing protein or repair a defective (e.g. truncated) one, these include an inherent risk of inducing adverse immune reactivity against the restored wild type protein, at least parts of which would be recognized in patients as foreign. For these reasons, only patients with residual expression of the EB-associated protein have been included in gene therapy trials to date [14, 16, 17, 19]. Despite this, transient circulating antibodies reactive against the gene-correction product, and also tissue-bound antibodies deposited within the graft, were reported in some participants [19, 20]. However, these did not correlate with rejection of the graft. In addition, a phenomenon called epitope spreading could theoretically occur in patients that mount an immune reaction against the gene-correction product, leading to autoimmunity against the endogenous mutated/residual protein present throughout the body’s epithelial tissues. This systemic immune reaction would likely manifest as blistering within the graft, as well as worsened blistering distal to the graft. Thus, monitoring immunological parameters (e.g. specific antibody formation) and diffuse new-onset blistering is warranted in study participants. While detailed immunological studies are still largely lacking, the results suggest ex vivo gene-replacement therapy to be a safe therapeutic approach in patients who lack pre-existing immune reactivity and express residual protein. However, future trials should aim to also include patients without any residual protein expression, who oftentimes display a more severe phenotype, and where there is likely no preexisting tolerance to prevent adverse immune reactions against the gene-correction product. Towards this goal, further research is required to exploit peripheral immune tolerance mechanisms to control the response to neo-antigens in the skin.
2.2 Treating complications of EB
While gene therapy is the only curative option for EB, strategies to ameliorate symptoms are critically needed to increase patient’s QoL and prevent severe complications of the disease until causal therapies are available for all EB patients. The number of preclinical and clinical studies published, including those currently registered, reflects the great effort placed into providing such. Strategies to identify suitable candidates are diverse, but great potential lies in drug repurposing, as this facilitates timely development of potent treatments by leveraging already existing pre-clinical and clinical data. Even so, the methodological challenges inherent to conducting studies in rare disease populations can complicate the clinical evaluation of repositioning such drugs for EB [69].
The active components of drugs generally comprise small molecules or biologics. While low molecular weight small molecules can be derived chemically and exhibit distinct advantages regarding delivery and route of administration, biologics, which are much larger, often interfere very specifically with distinct pathomechanisms and show overall less toxicity. Functionally, small molecules are frequently designed as inhibitors of e.g. enzymes, whereas biologics usually have a specific active function (e.g. antibodies, enzymes, nucleic acids).
In the context of EB several approaches addressing various complications have been reported, with the majority of primary outcomes measured being improvement of wound healing, reduction of blistering, and mitigation of itch. While some of the evaluated compounds have reached late stage clinical trials, first marketing approvals are still awaited [4, 5, 6, 7, 69].
2.2.1 Reduction of blistering
Across the various EB types, blistering of the skin may be the first clinical manifestation of skin fragility following mechanical friction or trauma. While in some patients blisters heal without scarring, in patients suffering from more severe subtypes these degenerate into wounds and are accompanied by multiple comorbidities. Thus, preventing blistering or accelerating their resolution is a logical primary outcome measure for clinical trials due to its relevance to patients, at least in distinct patient cohorts [7]. Particularly in EBS, where patients only rarely develop wounds, reducing blister numbers will improve patients’ QoL substantially. Especially during childhood, EBS patients are prone to developing numerous blisters, which may prevent children from e.g. learning to walk, or playing with other children. However, also for dystrophic and junctional EB clinical studies evaluating a treatment’s impact on blister numbers have been published [7].
For EBS, uncovering the pathways and molecular mediators underscoring the pathogenic keratin biology in cells, proved instrumental to the development of a topical formulation of the drug diacerein, which has been shown in randomized controlled trials (RCTs) to significantly reduce blister numbers in comparison to patients who received placebo [70, 71]. Moreover, during the patient follow-up period when no treatment was applied, a delayed recurrence of blisters was observed, pointing towards a long-term stabilization of the skin. Diacerein is a small molecule that interferes with the expression and signaling of the pro-inflammatory cytokine IL-1ß at various levels. Upregulation of IL-1ß, triggered by the accumulation of mutated keratins, is characteristic for distinct subtypes of EBS. However, the reciprocal effect of IL-1ß to further induce the expression of mutant keratins was also observed in patient cells. Thus, interfering with this positive feedback loop proved beneficial to stabilizing the keratinocyte’s intermediate filament network and consequently, also the patient’s skin [72].
2.2.2 Wound healing
EB patients develop wounds throughout their lifetime, and their management and daily care routine represent a major burden that is accompanied by substantial discomfort. There is currently no standard treatment for the treatment of non-healing or severely infected wounds in EB. Defects in wound healing, associated with infections and persistent inflammation are presumed major drivers of wound chronification, which is a major risk factor for the development of particularly aggressive squamous cell carcinomas (SCC) [2, 3]. Thus, means to improve wound healing, and thereby prevent downstream complications that severely decrease QoL and that may even be life-threatening, are urgently needed. This is also reflected by the high number of clinical trials that primarily aim to improve wound healing, either by applying drugs that modulate wound healing associated pathways (e.g. modulation of inflammation), or, if feasible, by directly targeting the EB-causing gene products using drugs that induce read-through of PTCs.
Promising outcomes were recently reported from a trial using anti-inflammatory/immunomodulatory betulin-rich birch bark extract (Filzuvez, previously Oleogel S-10), wherein 41.3% of patients treated with Oleogel-S10 met the primary endpoint of target wound closure within 45 (± 7) days as compared to 28.9% of patients within the placebo arm. Furthermore, among the EB subtypes evaluated, patients with RDEB appeared to be particularly responsive to treatment (NCT03068780). In the context of wound healing, induction of PTC read-through as a means of triggering re-expression of genes harboring nonsense mutations, is particularly attractive in cases where the drugs being evaluated for these purposes have known antibacterial and anti-inflammatory activity. Particularly for junctional and dystrophic EB patients, clinical trials investigating the aminoglycoside antibiotic gentamicin are still ongoing [43, 73, 74] (NCT04140786, NCT03526159, NCT04644627, NCT03392909). Additionally for RDEB, the anti-inflammatory, anti-allergic immunomodulator Amlexanox, typically used against mouth ulcers, has emerged as a novel candidate in preclinical studies [64].
2.2.3 Pruritus
Pruritus is a particularly agonizing aspect associated with all subtypes of EB which not only impairs patients’ QoL, but also leads to additional skin damage as it provokes scratching. Even though pruritus is not a life-threatening symptom per se, its overall influence on well-being is tremendous. In general, itch is a major problem associated with various diseases like atopic dermatitis, psoriasis, and nephrologic conditions. Yet, underlying molecular mechanisms are still not fully understood. Numerous inflammatory mediators have been associated with pathological itch, but despite pruritus being a severe clinical problem, effective treatments still represent an unmet medical need [75].
For patients with EB, a handful of studies targeting itch have been published, the most recent being a randomized-controlled trial (RCT) evaluating the neurokinin-1 receptor (NK1R) antagonist Serlopitant in patients with any EB subtype [76]. Serlopitant disrupts Substance P (SP) associated signaling by preventing its binding to NK1R. Expressed on multiple skin cell types, NK1R is thought to play a major role in the transmission of itch signals in the peripheral and central nervous systems [77]. In the RCT above, 14 EB patients received serlopitant or placebo over a period of 8 weeks, and reduction of pruritus was assessed using a numeric rating scale. Even though results were not statistically significant, patients who had received the investigational drug tended to achieve a ≥ 3 point reduction in itch compared to placebo, and a positive impact on QoL was reported by the patients. However, a larger clinical trial will be needed to provide clear evidence on the efficacy of serlopitant in reducing pruritus in patients with EB [76].
Another agent currently being evaluated against pruritus in patients with EB-pruriginosa is the anti-interleukin-4 receptor alpha (IL-4Rα) monoclonal antibody Dupilumab [78, 79]. Already indicated for atopic dermatitis, Dupilumab inhibits both IL-4 and IL-13 signaling and modulates Th2-mediated immune mechanisms. The promising outcome of both studies, which included a total of three patients, might provide a rationale for larger RCTs in the future that extend to other subtypes of EB.
Interestingly, in a single-patient observational study aimed primarily at investigating the wound healing benefits of a low-dose topical calcipotriol ointment in DEB, a significant reduction of itch was reported as a highly patient-relevant outcome. Calcipotriol is an analogue of the active form of vitamin D3, an important skin homeostasis factor with roles in cell proliferation, differentiation, antimicrobial defense, and immune modulation. Calcipotriol has proven anti-proliferative effects in keratinocytes, which is leveraged for the treatment of plaque psoriasis. For this reason, we investigated a lower concentration with respect to antimicrobial peptide induction in DEB keratinocytes. In addition to the complete closure of a chronic wound within two weeks of treatment, we observed significant improvement in the diversity of the skin microbiota on the treated skin area, with complete clearance of Staphylococcus aureus by the end of the treatment [80]. The low dose ointment was evaluated in a small double-blind, placebo-controlled phase II clinical trial (EudraCT: 2016–001967-35), where a significant and steady reduction in pruritus was observed with calcipotriol treatment compared to placebo [81]. These results support conducting a follow-up trial to investigate its impact on itch in patients with EB, particularly given calcipotriol’s reported anti-neoplastic effects.
2.2.4 Fibrosis
Repeated cycles of injury and subsequent persistent inflammation trigger a cascade of events leading to progressive fibrosis, followed by tissue stiffening and increased risk of tumor development in patients with dystrophic EB. Additionally, fibrotic webbing at limb extremities post-wounding ultimately leads to fusion of fingers and toes (called mitten deformities), severely limiting their use. Thus, strategies to support a normal course of wound healing are investigated to avoid or minimize deviations from deposition of a normal skin matrix [82]. A key player in EB-associated fibrosis is TGF-ß, a pro-inflammatory cytokine whose pleiotropic effects are highly context-dependent, and which has been shown to be constitutively expressed in RDEB-skin [83, 84]. While TGF-ß1 promotes wound healing under normal conditions, excessive TGF-ß1 signaling leads to abnormal ECM deposition and scar formation, as confirmed in a type VII collagen hypomorphic mouse model [85, 86]. Thus, modulating the expression of TGF-ß1 was hypothesized to be beneficial in reducing fibrosis. In this context, losartan, an angiotensin II antagonist with anti-fibrotic effects, has been evaluated in preclinical studies, where Nystrom et al achieved a significant reduction in fibrosis in collagen VII hypomorphic mice. This approach led to reduced TGF-ß signaling, normalized skin extracellular matrix composition, and delayed progression of mitten deformities [83]. Based on these results, a phase I/II clinical trial to evaluate the safety, tolerability and efficacy of losartan in children and adolescents with RDEB is currently underway (Eudra-CT: 2015–003670-32).
In a drug repurposing approach, endoglin (CD105), a type III co-receptor for TGF-1, and raloxifene, an estrogen receptor modulator, were tested in a pre-clinical setting for their potential to attenuate RDEB-associated fibrosis. Indeed, both drugs were shown to modulate profibrotic events, rendering them potential candidates for repositioning both compounds for the treatment of patients with EB [86].
2.3 EB-associated squamous cell carcinoma
Cutaneous tumors are a life-threatening complication that arise especially in patients with RDEB. Owing to the repeated cycles of wounding, infection and inflammation, RDEB patients are at especially high risk of developing aggressive squamous cell carcinoma (RDEB-SCC) with high risk-features. The sites of tumor occurrence are predominantly at sites of chronic and long-term wounds [87], especially on the extremities [88], indicating that tumorigenesis is related to the pathology of RDEB. The SCCs tend to arise in early adulthood, with a reported median age of 29 years at time of diagnosis, although the youngest case reported was in a 6-year old patient [89]. In comparison to the general population, RDEB patients have an estimated 70-fold higher risk of developing SCC [90], with cumulative risk rising from 7.5% at age 20 years, to 67.8% at age 35 years, to 90.1% by age 55 [2]. Despite aggressive therapy with multiple treatment modalities, median survival time from time of first diagnosis is 4–5 years [89], making RDEB-SCC the primary cause of premature death in these patients. The first choice of treatment still consists of wide local excision of the tumor, and even amputation of the extremity is sometimes necessary. Radiotherapy and conventional chemotherapeutic approaches have been mostly used palliatively in EB SCC and considering their strong adverse effects (e.g. desquamation of the skin upon radiotherapy) should be used carefully when applied to this vulnerable patient group [91].
Genomic analyses combined with transcriptomic profiling of tumors highlight cell endogenous mutagenic processes mediated by APOBEC enzymes, which are associated with an innate defense mechanism against ongoing microbial infection, as a major driver of carcinogenesis in RDEB. These observations indicate that effective wound management, which includes an antimicrobial component, could potentially lower cancer risk in these patients. Genetically, RDEB-SCC closely resembles ultraviolet (UV) light-induced SCC and SCC of the head and neck (HN-SCC), with driver mutations in known cancer-associated genes such as CASP8, NOTCH1, TP53, FAT1, CDKN2A, HRAS, ARID2, and KMT2B frequently observed [92]. While these similarities suggest that therapies proven to be efficacious in other SCCs would also be effective in RDEB SCC, careful consideration of the background pathology of EB is needed. The significant overlap in cellular processes associated with wound healing and tumor development (e.g. proliferation, migration, vascularisation/angiogenesis, matrix remodeling) dictates that a delicate balance needs to established wherein tumor inhibition is not interfering with wound healing, especially when long-term treatment is considered.
2.3.1 EGFR inhibition
Cetuximab, a monoclonal antibody targeting the extracellular domain of epidermal growth factor receptor (EGFR), has been used for therapy against both HN-SCC, as well as advanced unresectable cutaneous UV-SCC [93, 94]. This agent inhibits tumor cell proliferation by blocking receptor tyrosine kinase activity upstream of known survival-, growth-, and migration- signaling cascades mediated by PI3K/AKT, RAS/MAPK, and JAK/STAT [95, 96]. Cetuximab shows significant efficacy against EGFR-positive, wild type RAS tumors, while those bearing RAS mutations are resistant to treatment [97]. EB-associated SCCs frequently express EGFR, but with noticeable differences in expression level which could impact responsiveness to treatment [98]. To date, only a handful of cases have reported the use of cetuximab in EB patients with advanced cutaneous SCC, with limited beneficial effects on survival [88, 94, 98, 99, 100]. Progression-free survival in seven patients reported in the literature ranged from three weeks to nine months. Better outcomes have been observed when cetuximab was given as a first line treatment suggesting that treatment might be more efficacious when administered early. Of note, wound healing deficits and worsening of skin lesions, which negatively impact patient’s QoL, were noted in three patients. For one patient, the negative effects on patient wound healing led to a dose reduction of cetuximab and subsequent tumor recurrence soon after [98]. This negative impact of cetuximab in RDEB is likely associated with the important roles of the aforementioned downstream signaling cascades in wound healing processes and exemplifies the challenge of treating tumors in the background of EB. Thus, more targeted strategies, aimed at inhibition of tumor-essential pathways downstream of EGFR are already being investigated and are expected to minimize such adverse effects.
2.3.2 JAK1/2 inhibition
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway mediates cellular responses to a variety of cytokines and growth factors, including IL-6 and EGF, downstream of these ligands binding their cognate receptors. These responses include proliferation, differentiation, migration, survival, and apoptosis, and are dependent on cell- and tissue-type, as well as the context of the signal [101]. In this respect JAK/STAT plays important roles in developmental and homeostatic processes, and is also aberrantly active in numerous cancers, including HN-SCC [102]. Increased levels of phosphorylated STAT3, a downstream effector of JAK, were observed in RDEB-SCC cells over normal keratinocytes, providing rationale for evaluating the effect of the JAK1/2 inhibitor ruxolitinib in a murine xenograft model of human RDEB-SCC [103]. In this preclinical study, ruxolitinib effectively reduced tumor mass, when administered either orally or topically onto tumors, because reduced STAT3 signaling led to decreased cell proliferation. These observations argue that ruxolitinib may be a promising anticancer drug for RDEB-SCC. When ruxolitinib was used with the aim to counteract the fibrotic processes in the skin of type VII collagen hypomorphic mice, a reduction of phosphorylated STAT3 in fibroblasts and SCC in vitro, but only limited therapeutic benefit against fibrosis-driven mitten deformities in type VII collagen hypomorphic mice was observed [104]. Additionally, the drug was not well tolerated by the mice and, even more importantly, treatment delayed wound healing, highlighting that caution and rigorous evaluation is warranted before its clinical application in patients.
2.3.3 Polo-like kinase 1 inhibition
Due to the aggressive and metastasising nature of RDEB-SCC, which is atypical of UV-induced cutaneous SCCs that arise in the general population, gene expression assays were performed to identify differentially regulated genes that might account for this difference in tumor behavior. Among the handful of genes identified was polo-like kinase 1 (PLK1) [105], a serine/threonine protein kinase which was over-expressed in a number of different tumors [106]. Blocking PLK1 leads to mitotic arrest, inhibition of cell proliferation and apoptosis. Notably, cells were more sensitive to PLK1 inhibition when p53 was defective [107]. TP53 is frequently mutated in RDEB-SCC [92] highlighting PLK1-inhibition as a potential strategy to selectively target tumor cells over normal cells which exhibit normal p53 function. Several small molecules are under investigation for their ability to target PLK1 signaling in cancer, and results from these studies can be leveraged to facilitate the evaluation of these agents also for clinical use in RDEB patients. A study by Atansova et al., identified rigosertib (or ON-01910) among six different small-molecule inhibitors of PLK1 as a strong and selective inducer of apoptosis in RDEB-SCC cells. Its pre-clinical evaluation in a murine xenograft model demonstrated inhibition of tumor growth without obvious toxicity, laying the path for a multi-center phase II clinical trial in RDEB patients with late stage, metastatic, and/or unresectable SCC. [64] (NCT03786237).
2.3.4 Immune checkpoint blocking
Immune checkpoints are molecules that are either able to turn on (co-stimulatory molecules) or turn off (inhibitory molecules) immune signaling, generally referring to the activation of responses in T cells. Tumors have developed mechanisms to exploit these immune checkpoint molecules in order to evade immune surveillance and escape clearance by e.g. cytotoxic T cells [108]. Such immune checkpoint molecules include CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1 (programmed death-1). The latter is predominantly expressed on T cells, and by binding to its ligands PD-L1 and PD-L2 expressed on tumor cells, induces a negative signal that leads to effector T cell suppression [109]. Blocking these interactions using specific antibodies leads to reactivation of the immune system and improvement of anti-tumor immune responses. Remarkable anti-tumor effects were achieved with an antibody targeting CTLA-4 (ipilimumab), increasing median overall survival in metastatic melanoma patients [109]. Even better outcomes in survival rate have been observed with pembrolizumab, an anti-PD1 receptor antibody [110]. Furthermore, beneficial evidence in clinical trials using anti-PD1 treatment in advanced HN-SCC [111], and also locally advanced/metastatic SCC [112] support PD-1 blocking as well in RDEB SCC. In this respect, 2 reports can be found in the literature describing the use of anti-PD1 blocking antibodies in RDEB-SCC patients. The first case described the use of pembrolizumab (PD-1 antibody) as second line therapy after cetuximab treatment. Pembrolizumab was partly combined with other therapeutic approaches including intralesional administration of talimogene laherparepvec (T-Vec; oncolytic virus) into metastatic tumors, radiotherapy and anti-EGFR monoclonal antibody (panitumumab). Wound healing was not impaired during the late stage of the disease. The patient died due to tumor progression 18 months after starting pembrolizumab treatment [100]. Most recently, Khaddour et al. report on an RDEB patient with metastatic SCC who was treated with cemiplimab (monoclonal anti-PD1) every 3 weeks in combination with radiotherapy. During the 14-month follow-up the patient showed a durable response with no signs of immune-related adverse events [113]. These observations support conducting controlled clinical trials to assess the efficacy of PD-1 blockade in this patient group. Noteworthy, another anti-PD1 antibody (nivolumab) is currently under evaluation in a multi-centre phase II clinical trial for the palliative treatment of EB patients with advanced or metastatic squamous cell carcinomas (EudraCT: 2016–002811-16) [6].
3. Conclusions
In the last decade, the number of clinical trials registered for the evaluation of therapies against various primary and secondary pathologies associated with the various forms of EB has risen dramatically (>70 clinical trials; clinicaltrials.gov). They reflect the progress in the optimization of previous gene therapeutic approaches, discovery and advancement of novel gene editing technologies, and the increase in our understanding of the molecular and cellular mechanisms underpinning the nature of these EB-related complications. Drug repositioning has largely been prioritized, as leveraging the existing pharmacological and safety data represents the fastest and most economical route to clinical trials, and when successful, to marketing approval for EB. To further support the development of new therapy options for rare diseases like EB, several programs, like the orphan designation program by the European Medicines Agency (EMA) have been launched.
This is good news for patients, but also creates challenges for the recruitment of sufficient participants to the various trials, due to the rarity of the disease, strict inclusion criteria, and the disinclination of patients to participate. This heightens the risk of recruitment failure and the inability to meet statistical endpoints, resulting in extended trials that come at increased costs. Surmounting these challenges will require close collaboration within the entire EB community, to establish an international patient registry, incentivize patient participation, address logistical and regulatory aspects of multi-center trials, and allow for new outcome measures and the development of statistical methods for small cohorts. In parallel, applying current state-of-the-art methods that maximize acquisition of multi-modal data from patient samples, alongside the continuing advances in artificial intelligence, will further support the development of new therapies at various levels, starting from in silico drug discovery to establishing new means for measuring patient-relevant trial outcomes.
Acknowledgments
The authors would like to thank DEBRA Austria for their continued support and funding of our work. This work is generated within the ERN skin.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"Epidermolysis bullosa, genodermatoses, gene therapy, drug development, wound healing, pruritus, fibrosis, squamous cell carcinoma",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76441.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76441.xml",downloadPdfUrl:"/chapter/pdf-download/76441",previewPdfUrl:"/chapter/pdf-preview/76441",totalDownloads:258,totalViews:0,totalCrossrefCites:1,dateSubmitted:"December 15th 2020",dateReviewed:"March 26th 2021",datePrePublished:"April 27th 2021",datePublished:"September 22nd 2021",dateFinished:"April 24th 2021",readingETA:"0",abstract:"Although rare genodermatoses such as Epidermolysis bullosa have received more attention over the last years, no approved treatment options targeting causal mutations are currently available. Still, such diseases can be devastating, in some cases even associated with life-threatening secondary manifestations. Therefore, developing treatments that target disease-associated complications along with causal therapies remains the focus of current research efforts, in order to increase patient’s quality of life and potentially their life expectancy. Epidermolysis bullosa is a genodermatosis that is caused by mutations in either one of 16 genes, predominantly encoding structural components of the skin and mucosal epithelia that are crucial to give these barrier organs physical and mechanical resilience to stress. The genetic heterogeneity of the disease is recapitulated in the high variability of phenotypic expressivity observed, ranging from minor and localized blistering to generalized erosions and wound chronification, rendering certain subtypes a systemic disease that is complicated by a plethora of secondary manifestations. During the last decades, several studies have focused on developing treatments for EB patients and significant progress has been made, as reflected by numerous publications, patents, and registered trials available. Overall, strategies range from causal to symptom-relieving approaches, and include gene, RNA and cell therapies, as well as drug developments based on biologics and small molecules. In this chapter, we highlight the most recent and promising approaches that are currently being investigated in order to provide effective treatments for patients with epidermolysis bullosa in the future.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76441",risUrl:"/chapter/ris/76441",signatures:"Josefina Piñón Hofbauer, Verena Wally, Christina Guttmann-Gruber, Iris Gratz and Ulrich Koller",book:{id:"10545",type:"book",title:"Rare Diseases",subtitle:"Diagnostic and Therapeutic Odyssey",fullTitle:"Rare Diseases - Diagnostic and Therapeutic Odyssey",slug:"rare-diseases-diagnostic-and-therapeutic-odyssey",publishedDate:"September 22nd 2021",bookSignature:"Mani T. Valarmathi",coverURL:"https://cdn.intechopen.com/books/images_new/10545.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83969-412-7",printIsbn:"978-1-83962-930-3",pdfIsbn:"978-1-83969-413-4",isAvailableForWebshopOrdering:!0,editors:[{id:"69697",title:"Dr.",name:"Mani T.",middleName:null,surname:"Valarmathi",slug:"mani-t.-valarmathi",fullName:"Mani T. Valarmathi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"55757",title:"Dr.",name:"Verena",middleName:null,surname:"Wally",fullName:"Verena Wally",slug:"verena-wally",email:"v.wally@salk.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"55760",title:"Dr.",name:"Ulrich",middleName:null,surname:"Koller",fullName:"Ulrich Koller",slug:"ulrich-koller",email:"u.koller@salk.at",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55760/images/3392_n.jpg",institution:null},{id:"344925",title:"Dr.",name:"Christina",middleName:null,surname:"Gruber",fullName:"Christina Gruber",slug:"christina-gruber",email:"c.gruber@salk.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"344926",title:"Dr.",name:"Josefina",middleName:null,surname:"Piñón Hofbauer",fullName:"Josefina Piñón Hofbauer",slug:"josefina-pinon-hofbauer",email:"j.d.pinon@salk.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"348350",title:"Dr.",name:"Iris",middleName:null,surname:"Gratz",fullName:"Iris Gratz",slug:"iris-gratz",email:"iris.gratz@sbg.ac.at",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Therapy development for EB",level:"1"},{id:"sec_2_2",title:"2.1 Causal therapies for epidermolysis bullosa",level:"2"},{id:"sec_2_3",title:"Table 1.",level:"3"},{id:"sec_3_3",title:"2.1.2 Gene editing strategies for epidermolysis bullosa",level:"3"},{id:"sec_4_3",title:"2.1.3 RNA-based therapies for epidermolysis bullosa",level:"3"},{id:"sec_5_3",title:"2.1.4 Protein- and cell-based therapies for epidermolysis bullosa",level:"3"},{id:"sec_6_3",title:"2.1.5 Read-through strategies for epidermolysis bullosa",level:"3"},{id:"sec_7_3",title:"2.1.6 Immunological aspects of causal therapy",level:"3"},{id:"sec_9_2",title:"2.2 Treating complications of EB",level:"2"},{id:"sec_9_3",title:"2.2.1 Reduction of blistering",level:"3"},{id:"sec_10_3",title:"2.2.2 Wound healing",level:"3"},{id:"sec_11_3",title:"2.2.3 Pruritus",level:"3"},{id:"sec_12_3",title:"2.2.4 Fibrosis",level:"3"},{id:"sec_14_2",title:"2.3 EB-associated squamous cell carcinoma",level:"2"},{id:"sec_14_3",title:"2.3.1 EGFR inhibition",level:"3"},{id:"sec_15_3",title:"2.3.2 JAK1/2 inhibition",level:"3"},{id:"sec_16_3",title:"2.3.3 Polo-like kinase 1 inhibition",level:"3"},{id:"sec_17_3",title:"2.3.4 Immune checkpoint blocking",level:"3"},{id:"sec_20",title:"3. 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Department of Dermatology and Allergology, EB House Austria, Research Program for Molecular Therapy of Genodermatoses, University Hospital of the Paracelsus Medical University Salzburg, Austria
Department of Dermatology and Allergology, EB House Austria, Research Program for Molecular Therapy of Genodermatoses, University Hospital of the Paracelsus Medical University Salzburg, Austria
Department of Dermatology and Allergology, EB House Austria, Research Program for Molecular Therapy of Genodermatoses, University Hospital of the Paracelsus Medical University Salzburg, Austria
Department of Dermatology and Allergology, EB House Austria, Research Program for Molecular Therapy of Genodermatoses, University Hospital of the Paracelsus Medical University Salzburg, Austria
Department of Biosciences, University of Salzburg, Austria
Department of Dermatology and Allergology, EB House Austria, Research Program for Molecular Therapy of Genodermatoses, University Hospital of the Paracelsus Medical University Salzburg, Austria
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Tsiotas",authors:[{id:"106057",title:"Dr.",name:"Serafeim",middleName:null,surname:"Polyzos",slug:"serafeim-polyzos",fullName:"Serafeim Polyzos"}]},{id:"68541",doi:"10.5772/intechopen.88449",title:"Environmental Noise Mapping as a Smart Urban Tool Development",slug:"environmental-noise-mapping-as-a-smart-urban-tool-development",totalDownloads:999,totalCrossrefCites:3,totalDimensionsCites:5,abstract:"Since the European Directive 2002/49, large transportation infrastructure along with large urban areas should have completed strategic noise maps (SNM) and the relative noise action plans (NAP). The majority of European Member States (MS) has enforced this directive and completed fully or, in some cases, partially, with European smart cities to use and share the same criteria and methodologies and along with transport operators to communicate to the public the relevant results and respective action plans by ensuring the citizen’s awareness about the environmental noise, the quality acoustic environment, and their effect to their professional and everyday lifestyle. Today, 18 years after its first edition, the European Directive 2002/49/EC is needed to be reformulated to take into account all defects that have been identified and to adapt as well as possible to contemporary constraints. New methodology tools have been developed especially regarding soundscaping and environmental acoustic rehabilitation of urban areas, and the respective chapter will describe the progress being made on these smart developments of cities and infrastructures. This chapter will also evoke criticisms of these smart tools and will present results from several—state of the art—case studies especially regarding the practical and theoretical limits they face.",book:{id:"7624",slug:"smart-urban-development",title:"Smart Urban Development",fullTitle:"Smart Urban Development"},signatures:"Konstantinos Vogiatzis and Nicolas Remy",authors:null},{id:"63405",doi:"10.5772/intechopen.80810",title:"Restructuring Gauteng City Region in South Africa: Is a Transportation Solution the Answer?",slug:"restructuring-gauteng-city-region-in-south-africa-is-a-transportation-solution-the-answer-",totalDownloads:1856,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"The Gauteng city region forms the economic hub of socio-economic development and growth in South Africa. The province itself includes the Johannesburg metropolitan city, Ekurhuleni metropolitan city as well as Tshwane municipality—key urban growth regions of Gauteng province, South Africa, and by extension Southern Africa. The region exhibits the rapid urbanisation challenges typical in any developing country city. Rural–urban migration, pressure on infrastructure demand, supply and capacity constraints and mismatches in urban governance structures with respect to service delivery have remained stubborn challenges. Initiatives and strategies to resolve urban traffic congestion such as through road construction and highway expansion (physical instrument), e-tolling of roads (financial instrument), innovative housing and waste management technology deployment (technology instruments) as well as presenting advanced spatial planning and development and management systems (planning and regulatory instruments) have been employed with mixed fortunes in attempts to (re)solve the urban problems in the study area. Making use of a thematic approach and technique, the major urbanisation issues are explored and solutions proffered. Recommendations revolve around the need to implement robust and progressive rafts of projects, programmes, activities, measures and actions to reverse spatial fragmentation and spatially inefficient transport induced and perpetuated disadvantages.",book:{id:"7470",slug:"an-overview-of-urban-and-regional-planning",title:"An Overview of Urban and Regional Planning",fullTitle:"An Overview of Urban and Regional Planning"},signatures:"James Chakwizira, Peter Bikam and Thompson A. Adeboyejo",authors:[{id:"250792",title:"Dr.",name:"James",middleName:null,surname:"Chakwizira",slug:"james-chakwizira",fullName:"James Chakwizira"},{id:"265387",title:"Prof.",name:"Peter",middleName:null,surname:"Bikam",slug:"peter-bikam",fullName:"Peter Bikam"},{id:"265388",title:"Prof.",name:"Thompson A",middleName:null,surname:"Adeboyejo",slug:"thompson-a-adeboyejo",fullName:"Thompson A Adeboyejo"}]},{id:"34605",doi:"10.5772/35274",title:"Rainwater Harvesting in Large Residential Buildings in Australia",slug:"rainwater-harvesting-in-large-residential-buildings-in-australia",totalDownloads:4864,totalCrossrefCites:1,totalDimensionsCites:4,abstract:null,book:{id:"905",slug:"urban-development",title:"Urban Development",fullTitle:"Urban Development"},signatures:"Ataur Rahman, Joseph Dbais, Sk Mazharul Islam, Erhan Eroksuz and Khaled Haddad",authors:[{id:"89217",title:"Dr.",name:"Ataur",middleName:null,surname:"Rahman",slug:"ataur-rahman",fullName:"Ataur Rahman"},{id:"106643",title:"Mr.",name:"Erhan",middleName:null,surname:"Eroksuz",slug:"erhan-eroksuz",fullName:"Erhan Eroksuz"},{id:"106644",title:"Mr.",name:"Joseph",middleName:null,surname:"Dbais",slug:"joseph-dbais",fullName:"Joseph Dbais"},{id:"106646",title:"Mr.",name:"Khaled",middleName:null,surname:"Haddad",slug:"khaled-haddad",fullName:"Khaled Haddad"},{id:"106647",title:"Mr.",name:"Mazharul",middleName:null,surname:"Islam",slug:"mazharul-islam",fullName:"Mazharul Islam"}]}],mostDownloadedChaptersLast30Days:[{id:"69772",title:"Smart Rainwater Management: New Technologies and Innovation",slug:"smart-rainwater-management-new-technologies-and-innovation",totalDownloads:2012,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"In a smart city, the following factors are very vital such as smart grid and e-health. A smart city is one of the burning topics of research. Although there is no particular definition of a smart city, it means smart grid, e-health, e-environmental monitoring, smart home, smart water quality, smart air quality, etc. integrated into a single application. Human civilization can’t be sustained and prosper with shortage of usable water. Hence, water has a vital share in human life even for those living in smart cities. This chapter describes about the smart water quality issues in a smart city and some of the research advances in handling those issues. Among them it investigates the rainwater harvesting technologies and some of their practical applications.",book:{id:"7624",slug:"smart-urban-development",title:"Smart Urban Development",fullTitle:"Smart Urban Development"},signatures:"Raseswari Pradhan and Jayaprakash Sahoo",authors:null},{id:"62066",title:"Urban Planning and Mega-Event Projects: Lessons from Expo 2010, Shanghai",slug:"urban-planning-and-mega-event-projects-lessons-from-expo-2010-shanghai",totalDownloads:1335,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"With the capitalist transformation from Fordist-Keynesianism to neoliberalism, mega-events such as Olympic Games and World Exposition have increasingly been incorporated into urban development plan to boost urban renewal. Seeking the role of mega-event in urban transformation and its related effects have practical significance as mega-event movements have become a worldwide phenomenon. Although the profile of world fairs is reduced and does not have the international impacts that they used to have, Shanghai Expo 2010, the first Expo ever held in a developing country is pinned hope on as the “Turn to Save the World Expo” and is unusually ambitious to bring opportunities in urban transformation. While much attention has been paid to how mega-events can be used in tourism development in previous literature, this research links mega-event to urban development. Specifically, it reviews planning history before Expo 2010, addresses how a mega-event is integrated into city’s overall transformation strategy and what possible challenges a mega-event strategy may encounter related to the ultimate goal of urban transformation. It finds that political added value of mega-events empowers Shanghai to advance its urban agenda and the role of urban planner is vital to deliver a sustainable mega-event.",book:{id:"7470",slug:"an-overview-of-urban-and-regional-planning",title:"An Overview of Urban and Regional Planning",fullTitle:"An Overview of Urban and Regional Planning"},signatures:"Lingyue Li",authors:[{id:"247599",title:"Dr.",name:"Lingyue",middleName:null,surname:"Li",slug:"lingyue-li",fullName:"Lingyue Li"}]},{id:"67808",title:"Understanding Urban Mobility and Pedestrian Movement",slug:"understanding-urban-mobility-and-pedestrian-movement",totalDownloads:1371,totalCrossrefCites:2,totalDimensionsCites:4,abstract:"Urban environments continue to expand and mutate, both in terms of size of urban area and number of people commuting daily as well as the number of options for personal mobility. City layouts and infrastructure also change constantly, subject to both short-term and long-term imperatives. Transportation networks have attracted particular attention in recent years, due to efforts to incorporate “green” options, enabling positive lifestyle choices such as walking or cycling commutes. In this chapter we explore the pedestrian viewpoint, aids to familiarity with and ease of navigation in the urban environment, and the impact of novel modes of individual transport (as options such as smart urban bicycles and electric scooters increasingly become the norm). We discuss principal factors influencing rapid transit to daily and leisure destinations, such as schools, offices, parks, and entertainment venues, but also those which facilitate rapid evacuation and movement of large crowds from these locations, characterized by high occupation density or throughput. The focus of the chapter is on understanding and representing pedestrian behavior through the agent-based modeling paradigm, allowing both large numbers of individual actions with active awareness of the environment to be simulated and pedestrian group movements to be modeled on real urban networks, together with congestion and evacuation pattern visualization.",book:{id:"7624",slug:"smart-urban-development",title:"Smart Urban Development",fullTitle:"Smart Urban Development"},signatures:"Marija Bezbradica and Heather J. Ruskin",authors:null},{id:"63405",title:"Restructuring Gauteng City Region in South Africa: Is a Transportation Solution the Answer?",slug:"restructuring-gauteng-city-region-in-south-africa-is-a-transportation-solution-the-answer-",totalDownloads:1856,totalCrossrefCites:3,totalDimensionsCites:4,abstract:"The Gauteng city region forms the economic hub of socio-economic development and growth in South Africa. The province itself includes the Johannesburg metropolitan city, Ekurhuleni metropolitan city as well as Tshwane municipality—key urban growth regions of Gauteng province, South Africa, and by extension Southern Africa. The region exhibits the rapid urbanisation challenges typical in any developing country city. Rural–urban migration, pressure on infrastructure demand, supply and capacity constraints and mismatches in urban governance structures with respect to service delivery have remained stubborn challenges. Initiatives and strategies to resolve urban traffic congestion such as through road construction and highway expansion (physical instrument), e-tolling of roads (financial instrument), innovative housing and waste management technology deployment (technology instruments) as well as presenting advanced spatial planning and development and management systems (planning and regulatory instruments) have been employed with mixed fortunes in attempts to (re)solve the urban problems in the study area. Making use of a thematic approach and technique, the major urbanisation issues are explored and solutions proffered. Recommendations revolve around the need to implement robust and progressive rafts of projects, programmes, activities, measures and actions to reverse spatial fragmentation and spatially inefficient transport induced and perpetuated disadvantages.",book:{id:"7470",slug:"an-overview-of-urban-and-regional-planning",title:"An Overview of Urban and Regional Planning",fullTitle:"An Overview of Urban and Regional Planning"},signatures:"James Chakwizira, Peter Bikam and Thompson A. Adeboyejo",authors:[{id:"250792",title:"Dr.",name:"James",middleName:null,surname:"Chakwizira",slug:"james-chakwizira",fullName:"James Chakwizira"},{id:"265387",title:"Prof.",name:"Peter",middleName:null,surname:"Bikam",slug:"peter-bikam",fullName:"Peter Bikam"},{id:"265388",title:"Prof.",name:"Thompson A",middleName:null,surname:"Adeboyejo",slug:"thompson-a-adeboyejo",fullName:"Thompson A Adeboyejo"}]},{id:"62114",title:"Urban Noise as an Environmental Impact Factor in the Urban Planning Process",slug:"urban-noise-as-an-environmental-impact-factor-in-the-urban-planning-process",totalDownloads:1440,totalCrossrefCites:1,totalDimensionsCites:2,abstract:"This research focuses on an analysis of the perception of urban noise in the daily lives of the residents of two different areas: (1) a residential neighborhood and (2) a city center, respectively, considering (1) an acoustically ideal urban environment and (2) an acoustically polluted urban environment. To this end, a random sample of individuals from both areas was asked to fill out a questionnaire. Sound pressure levels were also measured in each of the evaluated areas. The World Health Organization (WHO) considers a quiet area as one in which the measured sound pressure level is up to 55 dB(A). The average measured sound pressure levels were 53.5 and 72.9 dB(A), respectively, in the quiet area and in the area considered acoustically polluted. Data were subjected to a multivariate factor analysis. The main complaints reported by the interviewees were as follows: headache, irritability, poor concentration and insomnia. Interviewees in the city center stated that street traffic noise was the main source of annoyance, while the residents of the residential area stated that the main source of discomfort was air traffic noise.",book:{id:"7470",slug:"an-overview-of-urban-and-regional-planning",title:"An Overview of Urban and Regional Planning",fullTitle:"An Overview of Urban and Regional Planning"},signatures:"Elaine Carvalho da Paz, Thomas Jeferson Vieira and Paulo Henrique Trombetta Zannin",authors:[{id:"66572",title:"Prof.",name:"Paulo Henrique Trombetta",middleName:null,surname:"Zannin",slug:"paulo-henrique-trombetta-zannin",fullName:"Paulo Henrique Trombetta Zannin"},{id:"257807",title:"MSc.",name:"Elaine Carvalho",middleName:null,surname:"Da Paz",slug:"elaine-carvalho-da-paz",fullName:"Elaine Carvalho Da Paz"},{id:"257814",title:"Mrs.",name:"Thomas Jeferson",middleName:null,surname:"Vieira",slug:"thomas-jeferson-vieira",fullName:"Thomas Jeferson Vieira"}]}],onlineFirstChaptersFilter:{topicId:"80",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:99,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:290,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:10,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:108,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:12,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:1,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:12,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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Ongoing issues, recent advances, and future diagnostic approaches and therapeutic strategies will also be discussed. This book series will focus on various aspects and properties of infectious diseases whose deep understanding is essential for safeguarding the human race from losing resources and economies due to pathogens.",coverUrl:"https://cdn.intechopen.com/series/covers/6.jpg",latestPublicationDate:"May 26th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:13,editor:{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"3",title:"Bacterial Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/3.jpg",isOpenForSubmission:!1,annualVolume:null,editor:null,editorTwo:null,editorThree:null},{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",isOpenForSubmission:!0,annualVolume:11400,editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,annualVolume:11401,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",isOpenForSubmission:!0,annualVolume:11402,editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. 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Radiotherapy and Nuclear Medicine Technology has always been my aspiration and my life. As years passed I accumulated a tremendous amount of skills and knowledge in Radiotherapy and Nuclear Medicine, Conventional Radiology, Radiation Protection, Bioinformatics Technology, PACS, Image processing, clinically and lecturing that will enable me to provide a valuable service to the community as a Researcher and Consultant in this field. My method of translating this into day to day in clinical practice is non-exhaustible and my habit of exchanging knowledge and expertise with others in those fields is the code and secret of success.",institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"313277",title:"Dr.",name:"Bartłomiej",middleName:null,surname:"Płaczek",slug:"bartlomiej-placzek",fullName:"Bartłomiej Płaczek",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/313277/images/system/313277.jpg",biography:"Bartłomiej Płaczek, MSc (2002), Ph.D. (2005), Habilitation (2016), is a professor at the University of Silesia, Institute of Computer Science, Poland, and an expert from the National Centre for Research and Development. His research interests include sensor networks, smart sensors, intelligent systems, and image processing with applications in healthcare and medicine. He is the author or co-author of more than seventy papers in peer-reviewed journals and conferences as well as the co-author of several books. He serves as a reviewer for many scientific journals, international conferences, and research foundations. Since 2010, Dr. Placzek has been a reviewer of grants and projects (including EU projects) in the field of information technologies.",institutionString:"University of Silesia",institution:{name:"University of Silesia",country:{name:"Poland"}}},{id:"35000",title:"Prof.",name:"Ulrich H.P",middleName:"H.P.",surname:"Fischer",slug:"ulrich-h.p-fischer",fullName:"Ulrich H.P Fischer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/35000/images/3052_n.jpg",biography:"Academic and Professional Background\nUlrich H. P. has Diploma and PhD degrees in Physics from the Free University Berlin, Germany. He has been working on research positions in the Heinrich-Hertz-Institute in Germany. Several international research projects has been performed with European partners from France, Netherlands, Norway and the UK. He is currently Professor of Communications Systems at the Harz University of Applied Sciences, Germany.\n\nPublications and Publishing\nHe has edited one book, a special interest book about ‘Optoelectronic Packaging’ (VDE, Berlin, Germany), and has published over 100 papers and is owner of several international patents for WDM over POF key elements.\n\nKey Research and Consulting Interests\nUlrich’s research activity has always been related to Spectroscopy and Optical Communications Technology. Specific current interests include the validation of complex instruments, and the application of VR technology to the development and testing of measurement systems. He has been reviewer for several publications of the Optical Society of America\\'s including Photonics Technology Letters and Applied Optics.\n\nPersonal Interests\nThese include motor cycling in a very relaxed manner and performing martial arts.",institutionString:null,institution:{name:"Charité",country:{name:"Germany"}}},{id:"341622",title:"Ph.D.",name:"Eduardo",middleName:null,surname:"Rojas Alvarez",slug:"eduardo-rojas-alvarez",fullName:"Eduardo Rojas Alvarez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/341622/images/15892_n.jpg",biography:null,institutionString:null,institution:{name:"University of Cuenca",country:{name:"Ecuador"}}},{id:"215610",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sarfraz",slug:"muhammad-sarfraz",fullName:"Muhammad Sarfraz",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/215610/images/system/215610.jpeg",biography:"Muhammad Sarfraz is a professor in the Department of Information Science, Kuwait University, Kuwait. His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. RELACION DE PONENCIAS DE LA SOCIEDAD ESPAÑOLA DE OFTALMOLOGIA. 10/2014.",institutionString:null,institution:null},{id:"265335",title:"Mr.",name:"Stefan",middleName:"Radnev",surname:"Stefanov",slug:"stefan-stefanov",fullName:"Stefan Stefanov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/265335/images/7562_n.jpg",biography:null,institutionString:null,institution:null},{id:"318905",title:"Prof.",name:"Elvis",middleName:"Kwason",surname:"Tiburu",slug:"elvis-tiburu",fullName:"Elvis Tiburu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Ghana",country:{name:"Ghana"}}},{id:"336193",title:"Dr.",name:"Abdullah",middleName:null,surname:"Alamoudi",slug:"abdullah-alamoudi",fullName:"Abdullah Alamoudi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Majmaah University",country:{name:"Saudi Arabia"}}},{id:"318657",title:"MSc.",name:"Isabell",middleName:null,surname:"Steuding",slug:"isabell-steuding",fullName:"Isabell Steuding",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"318656",title:"BSc.",name:"Peter",middleName:null,surname:"Kußmann",slug:"peter-kussmann",fullName:"Peter Kußmann",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Harz University of Applied Sciences",country:{name:"Germany"}}},{id:"338222",title:"Mrs.",name:"María José",middleName:null,surname:"Lucía Mudas",slug:"maria-jose-lucia-mudas",fullName:"María José Lucía Mudas",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}},{id:"147824",title:"Mr.",name:"Pablo",middleName:null,surname:"Revuelta Sanz",slug:"pablo-revuelta-sanz",fullName:"Pablo Revuelta Sanz",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Carlos III University of Madrid",country:{name:"Spain"}}}]}},subseries:{item:{id:"38",type:"subseries",title:"Pollution",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment",scope:"
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",hasOnlineFirst:!1,hasPublishedBooks:!0,annualVolume:11966,editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",slug:"ismail-m.m.-rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",biography:"Ismail Md. Mofizur Rahman (Ismail M. M. Rahman) assumed his current responsibilities as an Associate Professor at the Institute of Environmental Radioactivity, Fukushima University, Japan, in Oct 2015. He also has an honorary appointment to serve as a Collaborative Professor at Kanazawa University, Japan, from Mar 2015 to the present. \nFormerly, Dr. Rahman was a faculty member of the University of Chittagong, Bangladesh, affiliated with the Department of Chemistry (Oct 2002 to Mar 2012) and the Department of Applied Chemistry and Chemical Engineering (Mar 2012 to Sep 2015). Dr. Rahman was also adjunctly attached with Kanazawa University, Japan (Visiting Research Professor, Dec 2014 to Mar 2015; JSPS Postdoctoral Research Fellow, Apr 2012 to Mar 2014), and Tokyo Institute of Technology, Japan (TokyoTech-UNESCO Research Fellow, Oct 2004–Sep 2005). \nHe received his Ph.D. degree in Environmental Analytical Chemistry from Kanazawa University, Japan (2011). He also achieved a Diploma in Environment from the Tokyo Institute of Technology, Japan (2005). Besides, he has an M.Sc. degree in Applied Chemistry and a B.Sc. degree in Chemistry, all from the University of Chittagong, Bangladesh. \nDr. Rahman’s research interest includes the study of the fate and behavior of environmental pollutants in the biosphere; design of low energy and low burden environmental improvement (remediation) technology; implementation of sustainable waste management practices for treatment, handling, reuse, and ultimate residual disposition of solid wastes; nature and type of interactions in organic liquid mixtures for process engineering design applications.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",slug:"zinnat-ara-begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",biography:"Zinnat A. Begum received her Ph.D. in Environmental Analytical Chemistry from Kanazawa University in 2012. She achieved her Master of Science (M.Sc.) degree with a major in Applied Chemistry and a Bachelor of Science (B.Sc.) in Chemistry, all from the University of Chittagong, Bangladesh. Her work affiliations include Fukushima University, Japan (Visiting Research Fellow, Institute of Environmental Radioactivity: Mar 2016 to present), Southern University Bangladesh (Assistant Professor, Department of Civil Engineering: Jan 2015 to present), and Kanazawa University, Japan (Postdoctoral Fellow, Institute of Science and Engineering: Oct 2012 to Mar 2014; Research fellow, Venture Business Laboratory, Advanced Science and Social Co-Creation Promotion Organization: Apr 2018 to Mar 2021). The research focus of Dr. Zinnat includes the effect of the relative stability of metal-chelator complexes in the environmental remediation process designs and the development of eco-friendly soil washing techniques using biodegradable chelators.",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,series:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713"},editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",slug:"meng-chuan-ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",slug:"mohamed-nageeb-rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",slug:"olga-anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},onlineFirstChapters:{paginationCount:1,paginationItems:[{id:"81999",title:"Climate Change, Rural Livelihoods, and Human Well-Being: Experiences from Kenya",doi:"10.5772/intechopen.104965",signatures:"André J. 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models and developments are based on the knowledge generation on applied intelligence. The motor of the society is the industry and the research of this topic has to be empowered in order to increase and improve the quality of our lives.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/22.jpg",keywords:"Machine Learning, Intelligence Algorithms, Data Science, Artificial Intelligence, Applications on Applied Intelligence"},{id:"23",title:"Computational Neuroscience",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. Particularly interesting are models of various types of more compound functions and abilities, various and more general fundamental principles (e.g., regarding architecture, organization, learning, development, etc.) found at various spatial and temporal levels.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/23.jpg",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness"},{id:"24",title:"Computer Vision",scope:"The scope of this topic is to disseminate the recent advances in the rapidly growing field of computer vision from both the theoretical and practical points of view. Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",keywords:"Image Analysis, Scene Understanding, Biometrics, Deep Learning, Software Implementation, Hardware Implementation, Natural Images, Medical Images, Robotics, VR/AR"},{id:"25",title:"Evolutionary Computation",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",keywords:"Genetic Algorithms, Genetic Programming, Evolutionary Programming, Evolution Strategies, Hybrid Algorithms, Bioinspired Metaheuristics, Ant Colony Optimization, Evolutionary Learning, Hyperparameter Optimization"},{id:"26",title:"Machine Learning and Data Mining",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems. \r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
",coverUrl:"https://cdn.intechopen.com/series/covers/25.jpg",latestPublicationDate:"April 13th, 2022",hasOnlineFirst:!1,numberOfOpenTopics:4,numberOfPublishedChapters:9,numberOfPublishedBooks:1,editor:{id:"197485",title:"Dr.",name:"J. Kevin",middleName:null,surname:"Summers",fullName:"J. Kevin Summers",profilePictureURL:"https://mts.intechopen.com/storage/users/197485/images/system/197485.jpg",biography:"J. Kevin Summers is a Senior Research Ecologist at the Environmental Protection Agency’s (EPA) Gulf Ecosystem Measurement and Modeling Division. He is currently working with colleagues in the Sustainable and Healthy Communities Program to develop an index of community resilience to natural hazards, an index of human well-being that can be linked to changes in the ecosystem, social and economic services, and a community sustainability tool for communities with populations under 40,000. He leads research efforts for indicator and indices development. Dr. Summers is a systems ecologist and began his career at the EPA in 1989 and has worked in various programs and capacities. This includes leading the National Coastal Assessment in collaboration with the Office of Water which culminated in the award-winning National Coastal Condition Report series (four volumes between 2001 and 2012), and which integrates water quality, sediment quality, habitat, and biological data to assess the ecosystem condition of the United States estuaries. He was acting National Program Director for Ecology for the EPA between 2004 and 2006. He has authored approximately 150 peer-reviewed journal articles, book chapters, and reports and has received many awards for technical accomplishments from the EPA and from outside of the agency. Dr. Summers holds a BA in Zoology and Psychology, an MA in Ecology, and Ph.D. in Systems Ecology/Biology.",institutionString:null,institution:{name:"Environmental Protection Agency",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"38",title:"Pollution",keywords:"Human activity, Pollutants, Reduced risks, Population growth, Waste disposal, Remediation, Clean environment",scope:"
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
",annualVolume:11966,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/38.jpg",editor:{id:"110740",title:"Dr.",name:"Ismail M.M.",middleName:null,surname:"Rahman",fullName:"Ismail M.M. Rahman",profilePictureURL:"https://mts.intechopen.com/storage/users/110740/images/2319_n.jpg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorTwo:{id:"201020",title:"Dr.",name:"Zinnat Ara",middleName:null,surname:"Begum",fullName:"Zinnat Ara Begum",profilePictureURL:"https://mts.intechopen.com/storage/users/201020/images/system/201020.jpeg",institutionString:null,institution:{name:"Fukushima University",institutionURL:null,country:{name:"Japan"}}},editorThree:null,editorialBoard:[{id:"252368",title:"Dr.",name:"Meng-Chuan",middleName:null,surname:"Ong",fullName:"Meng-Chuan Ong",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRVotQAG/Profile_Picture_2022-05-20T12:04:28.jpg",institutionString:null,institution:{name:"Universiti Malaysia Terengganu",institutionURL:null,country:{name:"Malaysia"}}},{id:"63465",title:"Prof.",name:"Mohamed Nageeb",middleName:null,surname:"Rashed",fullName:"Mohamed Nageeb Rashed",profilePictureURL:"https://mts.intechopen.com/storage/users/63465/images/system/63465.gif",institutionString:null,institution:{name:"Aswan University",institutionURL:null,country:{name:"Egypt"}}},{id:"187907",title:"Dr.",name:"Olga",middleName:null,surname:"Anne",fullName:"Olga Anne",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBE5QAO/Profile_Picture_2022-04-07T09:42:13.png",institutionString:null,institution:{name:"Klaipeda State University of Applied Sciences",institutionURL:null,country:{name:"Lithuania"}}}]},{id:"39",title:"Environmental Resilience and Management",keywords:"Anthropic effects, Overexploitation, Biodiversity loss, Degradation, Inadequate Management, SDGs adequate practices",scope:"
\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
",annualVolume:11967,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"
\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
",annualVolume:11968,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/40.jpg",editor:{id:"209149",title:"Prof.",name:"Salustiano",middleName:null,surname:"Mato",fullName:"Salustiano Mato",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRLREQA4/Profile_Picture_2022-03-31T10:23:50.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorTwo:{id:"60498",title:"Prof.",name:"Josefina",middleName:null,surname:"Garrido",fullName:"Josefina Garrido",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRj1VQAS/Profile_Picture_2022-03-31T10:06:51.jpg",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorThree:{id:"464288",title:"Dr.",name:"Francisco",middleName:null,surname:"Ramil",fullName:"Francisco Ramil",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003RI7lHQAT/Profile_Picture_2022-03-31T10:15:35.png",institutionString:null,institution:{name:"University of Vigo",institutionURL:null,country:{name:"Spain"}}},editorialBoard:[{id:"220987",title:"Dr.",name:"António",middleName:"Onofre",surname:"Soares",fullName:"António Soares",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNtzQAG/Profile_Picture_1644499672340",institutionString:null,institution:{name:"University of the Azores",institutionURL:null,country:{name:"Portugal"}}}]},{id:"41",title:"Water Science",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection",scope:"
\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
\r\n
\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
",annualVolume:11969,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",editor:{id:"349630",title:"Dr.",name:"Yizi",middleName:null,surname:"Shang",fullName:"Yizi Shang",profilePictureURL:"https://mts.intechopen.com/storage/users/349630/images/system/349630.jpg",institutionString:"China Institute of Water Resources and Hydropower Research",institution:{name:"China Institute of Water Resources and Hydropower Research",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"216491",title:"Dr.",name:"Charalampos",middleName:null,surname:"Skoulikaris",fullName:"Charalampos Skoulikaris",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRMsbQAG/Profile_Picture_2022-04-21T09:31:55.jpg",institutionString:null,institution:{name:"Aristotle University of Thessaloniki",institutionURL:null,country:{name:"Greece"}}},{id:"300124",title:"Prof.",name:"Thomas",middleName:null,surname:"Shahady",fullName:"Thomas Shahady",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002kuIgmQAE/Profile_Picture_2022-03-18T07:32:10.jpg",institutionString:null,institution:{name:"Lynchburg College",institutionURL:null,country:{name:"United States of America"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/28705",hash:"",query:{},params:{id:"28705"},fullPath:"/chapters/28705",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()