Thermophysical properties of some common PCMs with high latent heat.
\r\n\tThis book is intended to provide a series of peer reviewed chapters that the guest editor believe will aid in increasing the quality of the research focus across the growing field of grain and seeds compound functionality research. Overall, the objective of this project is to serve as a reference book and as an excellent resource for students, researchers, and scientists interested and working in different functional aspects of grain and seed compounds, and particularly for the scientific community to encourage it to continue publishing their research findings on grain and seed and to provide basis for new research, and the area of sustainable crop production.
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Induced pluripotent stem cells (iPSC) are generated by reprogramming differentiated somatic cells to a pluripotent cell state that highly resembles embryonic stem cells (ESC) [1]. Fully reprogrammed iPSC can differentiate into any adult cell type [2-6]. Takahashi and Yamanaka generated the first iPSC in 2006 by transfecting fibroblasts with four defined factors: SOX2, OCT4, KLF4, c-MYC (SOKM; also referred to as Yamanaka factors) [7]. The clinical use of iPSC offers great potential for regenerative medicine as any cell type can be generated from true pluripotent cells [8-10]. However, human clinical iPSC applications are currently limited by inefficient methods of reprogramming that often generate incompletely reprogrammed pluripotent states that harbor potentially cancerous epigenetic signatures, and possess limited or skewed differentiation capacities [11-13]. Many standard iPSC lines do not fully resemble pluripotent ESC, and often retain an epigenetic memory of their cell of origin [14, 15]. Such incompletely reprogrammed iPSC also display limited differentiation potential to all three germ layers (e.g., endoderm, ectoderm, mesoderm) [16, 17].
To avoid integrating retroviral constructs that may carry mutagenic risks, many non-viral methods have been described for hiPSC derivation [18, 19]. For example, one successful approach is to transiently express reprogramming factors with EBNA1-based episomal vectors [20-22]. It was initially intuitive to reprogram skin fibroblasts due to their easy accessibility. However, standard episomal reprogramming in fibroblasts occurs at even lower efficiencies (< 0.001-0.1%) than reprogramming with retroviral vectors (0.1%–1%) [23-25]. Subsequent studies revealed that various cell types possess differential receptiveness for being reprogrammed to pluripotency [26-30]. One highly accessible human donor source is blood, which has been demonstrated to reprogram with significantly greater efficiency than fibroblasts [4, 20, 31-33].
The innate immune system possesses highly flexible cell types that are able to adapt quickly to various pathogens by eliciting defense responses that protect the host [34-36]. Innate immune cells derived from the myeloid lineage (eg, monocyte-macrophage, dendritic cells, neutrophils) are able to reactivate some unique features of pluripotent stem cells that may give them greater flexibility for being reprogrammed to a pluripotent cell state than other differentiated cells [37]. Additionally, the differentiation state of the cell seems to be of critical importance for its reprogramming efficiency [38].
Our group established a reprogramming method that solves many of the technical caveats cited above (Figure 1). We have generated high-fidelity human iPSC (hiPSC) from stromal-primed (sp) myeloid progenitors [20]. This system can reprogram >50% of episome-expressing myeloid cells to high-quality hiPSC characterized by minimal retention of hematopoietic-specific epigenetic memory and a molecular signature that is indistinguishable from bona fide human ESC (hESC). The use of bone marrow-, peripheral-or cord blood (CB)-derived myeloid progenitor cells instead of fibroblasts, and a brief priming step on human bone marrow stromal cells / mesenchymal stem cells (MSC) appeared to be critical for this augmented reprogramming efficiency. In this system, CD34+ - enriched cord blood cells (CB) are expanded with the growth factors (GF) FLT3L (FMS-like tyrosine kinase 3 ligand), SCF (stem cell factor) and TPO (thrombopoietin) for 3 days, subsequently nucleofected with non-integrating episomes expressing the Yamanaka factors (4F, SOX2, OCT4, KLF4, c-MYC), and then co-cultured on irradiated MSC for an additional 3 days. Cells are then harvested, and passaged onto MEF (mouse embryonic fibroblasts), and hiPSC are generated via standard methods and culture medium. The initial population of enriched CD34+ CB progenitors quickly differentiates to myeloid and monocytic cells in this system, and reprogrammed cells arise from CD34- myeloid cells. The first iPSC colonies appear around day 10, and stable mature iPSC colonies can be established after ~21-25 days. The episomal constructs are partitioned after relatively few cell divisions (e.g., 2-9 passages) to generate high quality non-integrated hiPSC.
Schema of the stromal-primed myeloid reprogramming protocol for the generation of high quality human iPSC. 4F: four Yamanaka factors, GF: hematopoietic growth factors.
A proteomics and bioinformatics analysis of this reprogramming system implicated significant activation of MSC-induced inflammatory TLR-NFκB and STAT3 signaling [20]. A combination of cell contact-dependent and soluble factors mediate these effects. A recent study similarly implicated inflammatory TLR3 signaling as a novel trigger for enhanced fibroblast reprogramming, albeit at much lesser efficiencies than observed in our myeloid reprogramming system. TLR3 signaling leads to epigenetic modifications that favor an open chromatin state, which increases cell plasticity and the induction of pluripotency [39]. Lee et al. termed this novel link between inflammatory pathways and cell reprogramming ‘Transflammation’ [40].
In this chapter we will discuss hypotheses why inflammation-activated myeloid cells may be highly receptive to factor-mediated reprogramming. Specifically, we will explore the role of the NFκB-STAT3 signaling axis in mediating the unique susceptibility of myeloid cells to high-quality human iPSC derivation.
Multipotent myeloid progenitors are derived from hematopoietic stem cells and differentiate to monocytes macrophages, dendritic cells, and granulocytes, which elicit the initial innate immune response toward pathogens [41]. NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a central transcription factor that regulates these innate immune responses during microbial infections [42-44]. The NFκB system belongs to a group of early-acting transcription factors that are present in the cytoplasm in an inactive state but can be quickly activated by multiple inflammatory stimuli [45, 46].
The NFκB family consists of 5 members; p65 (RelA), p50 and c-Rel are involved in canonical signaling, and p52 and RelB are involved in non-canonical signaling. Canonical NFκB signaling is characterized by activation of the IκB kinase complex (IKK), which contains two kinases, IKK1/α and IKK2/β along with a non-catalytic subunit called IKKγ (NEMO) [47, 48]. Unstimulated NFκB is sequestered in the cytoplasm by IκBα protein. In contrast, activation of the IKK complex (e.g., by TLRs) leads to IKKβ-mediated serine phosphorylation of IκBα triggering its proteasome-mediated degradation and its dissociation from NFκB [49, 50]. This activates the p65:p50 dimer through p65 phosphorylation and leads to NFκB translocation into the nucleus where it induces target gene expression. Subsequent acetylation keeps p65 in the nucleus [51]. This can be reverted by HDAC3 (histone deacetylase 3)-induced deacetylation of p65, which increases the affinity of NFκB proteins for IκBα and nuclear export [52, 53]. Canonical NFκB signaling is a fast and transient process that regulates complex inflammatory processes that includes the initial pro-inflammatory phase, the induction of apoptosis, and even tumorigenesis [54]. It can be activated by toll-like receptors (TLR), which recognize characteristic pathogenic molecules to activate innate immune responses [55-57].
Non-canonical NFκB signaling is stimulated via the NFκB-inducing kinase (NIK), which leads to phosphorylation of the p100 precursor protein and generation of the p52:RelB dimer that translocates to the nucleus to activate gene transcription. This pathway is uniquely dependent on steady state levels of NIK expression, which are controlled under normal conditions through TRAF3-directed ubiquitination and proteasomal degradation. Non-canonical NFκB signaling is slow but persistent and requires de novo NIK protein synthesis and NIK stabilization [58]. It is activated by receptors that belong to the TNFR (tumor necrosis factor receptor) superfamily like BAFF (B-cell-activating factor), CD40 or lymphotoxin β-receptor (LTβR) [59-62].
The common feature of these receptors is the possession of a TRAF-binding motif, which recruits TRAF members (e.g., TRAF2 and TRAF3) during ligand ligation [63, 64]. Receptor recruitment of TRAF members triggers their degradation, and leads to NIK activation and p100 processing [65]. Additionally, BAFF is an important component of pluripotency-supporting growth media for the culture of ESC and a regulator of B-cell maturation [66]. It predominantly activates non-canonical NFκB signaling due to its possession of an atypical TRAF-binding sequence, which interacts only with TRAF3 but not with TRAF2 [67]. TRAF3 degradation is sufficient to trigger non-canonical NFκB signaling, whereby activation of the canonical NFκB pathway requires TRAF2 recruitment [68].
Another receptor associated with NFκB signaling is CD40, which is expressed on various cell types including B cells and monocytes. The CD40 receptor interacts with its ligand CD40L, which is primarily expressed on activated T cells. This signaling is majorly involved in B-cell activation, dendritic cell maturation, antigen presentation and acts as a co-stimulatory pathway of T-cells [69]. Upon ligation by CD40L, CD40 targets both the canonical and non-canonical NFκB pathways via proteolysis of TRAF2 and TRAF3 [70-72]. Non-canonical NFκB signaling regulates hematopoietic stem cell self-renewal via regulating their interactions with the microenvironment [73]. The deregulation of non-canonical hematopoietic NFκB signaling is associated with auto-immunity, inflammation and lymphoid malignancies [58, 74].
A third NFκB signaling pathway is activated following response to DNA damage that results in IκB degradation independent of IKK. This results in dimerization of free NFκB subunits that are mobilized similarly to canonical NFκB signaling [47]. Unlike RelA, RelB, and c-Rel, the p50 and p52 NFκB subunits do not contain transactivation domains in their C-terminus. Nevertheless, the p50 and p52 NFκB members play critical roles in modulating the specificity of NFκB functions and form heterodimers with RelA, RelB, or c-Rel [75]. Cell contact-dependent signals are crucial during immune responses and can be mediated through NFκB signaling [76]. This can be augmented by co-stimulatory signals like CD40 or CD28 that directly bind to NFκB proteins like p65 [77-81].
TLR activation is not only important for mediating innate immune responses, but also for stem cell differentiation. For example, hESC are characterized by the expression of pluripotency genes and markers such as OCT4, NANOG, alkaline phosphatase (AP) and telomerase [82-86]. NFκB signaling has been demonstrated to be crucial for maintaining ESC pluripotency and viability, and drives lineage-specific differentiation [87, 88]. A balance of canonical and non-canonical NFκB signaling regulates these opposing functions; non-canonical pathway signaling maintains hESC pluripotency, and canonical pathway signaling regulates hESC viability and differentiation [89, 90]. For example, non-canonical NFκB signaling has to be silenced during cell differentiation, which allows this pathway to act like a switch between hESC self-renewal and differentiation. RelB positively regulates several key pluripotency markers and represses lineage markers by direct binding to their regulatory units. RelB down-regulation reduces the expression of pluripotency genes like SOX2 and induces differentiation-associated genes like BRACHYURY (mesodermal marker), CDX2 (trophoectodermal marker) and GATA6 (endodermal marker) [89].
RelB/p52 signaling also positively regulates hematopoietic stem-progenitor cell (HSPC) self-renewal in response to cytokines (e.g., TPO and SCF) and maintains osteoblast niches and the bone marrow stromal cell population. It negatively regulates HSPC lineage commitment through cytokine down-regulation in the bone marrow microenvironment, although it is able to direct early HSC commitment to the myeloid lineage [73, 91].
Canonical p65 signaling also regulates hematopoietic stem cell functions and lineage commitment by controlling key factors involved in hematopoietic cell fate [92-94]. Canonical NFκB signaling is positively regulated by Notch1, which facilitates nuclear retention of NFκB proteins and promotes self-renewal [95-98]. FGF2 (fibroblast growth factor 2) is important for hESC self-renewal and preserves the long-term repopulating ability of HSPC through NFκB activation [99-102]. Deletion of p65, p52 and RelB dramatically decreases HSC differentiation, function and leads to extramedullary hematopoiesis [103]. NFκB pathway components and FGF4 are highly expressed in CD34+HSPC from cord blood, where they regulate clonogenicity. Nuclear p65 can be detected in 90% CB-derived CD34+ cells but only in 50% BM-derived CD34+ cells [104]. The important role of NFκB in regulating myeloid cell lineage development has been most potently revealed via genetic deletion of IKKβ, IκBα, and RelB, which resulted in granulocytosis, splenomegaly and impaired immune responses [73, 103].
Canonical NFκB signaling is very low in the undifferentiated pluripotent state, where it maintains hESC viability. However, it strongly increases during lineage-specific differentiation of pluripotent stem cells. p65 binds to the regulatory regions of similar differentiation genes as RelB with opposing effects on their activation or silencing. It regulates cell proliferation by direct binding to the CYCLIN D1 promoter [89]. There are different levels of inhibiting canonical NFκB signaling: first, p65 translational repression by the microRNA cluster miR-290 to maintain low p65 protein amounts and second, the inhibition of translated p65 by physical interaction with NANOG. Similarly, OCT4 expression is reversely correlated with canonical NFκB signaling [105]. In contrast to most observations in mouse ESC, NFκB probably plays a more important role in the maintenance of human ESC pluripotency [106]. Finally, active TLRs are expressed on embryonic, hematopoietic and mesenchymal stem cells (MSC), thus implicating their roles in a variety of stem cell types [107-110].
Undifferentiated human iPSC have elevated NFκB activities, which play important roles in maintaining OCT4 and NANOG expression in pluripotent hiPSC [111]. Innate immune TLR signaling was recently shown to enhance nuclear reprogramming probably through the induction of an open chromatin state, and global changes of epigenetic modifiers [39]. This normally increases cell plasticity in response to a pathogen, but may also enhance the induction of pluripotency, transdifferentiation and even malignant transformation [112-116].
The EBNA (Epstein-Barr virus nuclear antigen) is a virus-derived protein that is not only a critical component of episomal reprogramming vectors, where it mediates extra-chromosomal self-replication, but it is also known to activate several TLRs [117-119]. These include TLR3, which is known to augment reprogramming efficiencies through the activation of inflammatory pathways [39, 120]. TLR3 recognizes double-stranded RNA from retroviruses and signals through TRAF6 and NFκB [121-123]. The TLR3 agonist poly I:C was shown to have the same effect as retroviral particles in enhancing Yamanaka factor-induced iPSC production. TLR3 causes widespread changes in the expression of epigenetic modifiers and facilitates nuclear reprogramming by inducing an open chromatin state through down-regulation of histone deacetylases (HDACs) and H3K4 (histone H3 at lysine 4) trimethylations [38, 39, 124]. These epigenetic modifications mark transcriptionally active genes, whereas the H3K9me3 (Histone H3 at lysine 9) modification marks transcriptionally silenced genes [125, 126]. Histone deacetylation is generally associated with a closed chromatin state and HDAC inhibitors were shown to enhance nuclear reprogramming [127, 128]. Histone acetylation favors an open chromatin state, and is maintained by proteins containing histone acetyltransferase (HAT) domains, such as p300 and CBP [129, 130]. Interestingly, p300/CBP is able to interact with NFκB [131, 132]. RelB directly interacts with the methyltransferase G9a to mediate gene silencing of differentiation genes [133]. Epigenetic changes that allow an open chromatin state are crucial for giving the Yamanaka factors access to promoter regions necessary for the induction of pluripotency. Epigenetic chromatin modifications by TLRs are normally involved in the expression of host defense genes during infections [134-136]. This capability can be deployed to enable nuclear reprogramming as TLR3 was shown to change the methylation status of the Oct4 and Sox2 promoters. Interestingly, changes in these methylation marks were not observed with TLR3 activation alone but only in the presence of the reprogramming factors. Although TLR3 by itself promotes an open chromatin configuration, the reprogramming proteins are likely necessary to direct the epigenetic modifiers to the appropriate promoter sequences [137]. Lee et al. described the potential of inflammatory pathways to facilitate the induction of pluripotency as ‘transflammation’ [40, 138].
The JAK/STAT pathway (Janus kinase/signal transducer and activator of transcription) integrates a complex network of exterior signals into the cell, and can be activated by a variety of ligands and their receptors [139]. These receptors are associated with a JAK tyrosine kinase at their cytoplasmic domain. The JAK family consists of the four members JAK1, JAK2, JAK3 and TYK2 [140, 141]. Many cytokines and growth factors signal through this pathway to regulate immune responses, cell proliferation, differentiation and apoptosis [142-146]. Ligand binding induces the multimerization of gp130 receptor subunits, which brings two JAKs close to each other inducing trans-phosphorylation. Such activated JAKs phosphorylate their receptor at the C-terminus and the transcription factor STAT at tyrosine residues. This allows STAT dimerization and their nuclear translocation to induce target gene transcription. [147, 148] STAT3 acetylation is critical for stable dimer formation and DNA binding [149]. From the 7 mammalian STATs, STAT3 and STAT5 are expressed in many cell types, are activated by a plethora of cytokines and growth factors, and integrate complex biological signals [150, 151]. The other STAT proteins mainly play specific roles in the immune response to bacterial and viral infections. STAT3 is an acute phase protein with important functions during immediate immune reactions [152-154]. STAT3 can be recruited by receptor tyrosine kinases that harbor a common STAT3 binding motif in their cytoplasmic domain (e.g., GCSF (granulocyte colony-stimulating factor), LIF (leukemia inhibitory factor), EGF (epidermal growth factor), PDGF (platelet-derived growth factor), interferons (IFNγ) and interleukins (IL-6, IL-10)) [155-158]. Many cytokines signal through IL-10/STAT3 to achieve an immunosuppressive function or anti-apoptotic effect [159, 160]. IL-10 is also required during terminal differentiation of immunoglobulins [161]. STAT3 can be phosphorylated at tyrosine or serine residues. The phosphorylation site can play distinct roles in the regulation of downstream gene transcription [162]. Stat3-deficient mice die during early embryogenesis due to Stat3 requirement for the self-renewal of ESC [163].
Negative feedback regulation of the JAK/STAT circuitry is mediated by the SOCS family of target genes (suppressors of cytokine signaling) in a way that activated STAT induces SOCS transcription [164, 165]. SOCS proteins can bind to phosphorylated JAKs as a pseudo-substrate to inhibit JAK kinase activity and turn off the pathway [166, 167]. SOCS are negative regulators of the immune response [168, 169]. A small peptide antagonist of SOCS1 was shown to bind to the activation loop of JAK2 leading to constitutive STAT activation and TLR3 induction. This boosts the immune system to exert broad antiviral activities [170]. The JAK/STAT pathway also interacts with many other signaling pathways in a complex manner to regulate cell homeostasis and immune reactions [149, 171].
ESC pluripotency is regulated by transcriptional networks that maintain self-renewal and inhibit differentiation [172-174]. Stat3 and Myc are necessary to maintain mouse ESC (mESC) self-renewal and bind to many ESC-enriched genes [175]. Their target genes include pluripotency-related transcription factors, polycomb group repressive proteins, and histone modifiers [176, 177]. The transcription factor Stat3 is a key pluripotency factor required for ESC self-renewal [178, 179]. Mouse ESC require LIF-Stat3 (leukemia inhibitory factor) and Bmp4 (bone morphogenic protein 4) to remain pluripotent in in vitro cultures, whereas human ESC require FGF2/MAPK (fibroblast growth factor / mitogen-activated protein kinase) and TGFβ/Activin/Nodal (transforming growth factor β) [180-183]. Nevertheless, the core circuitry of pluripotency is conserved among species and includes OCT4, SOX2 and NANOG [174].
LIF belongs to the IL-6 family of cytokines and acts in parallel through the Jak/Stat3 and PI3K/Akt (Phosphatidylinositide 3-kinase) pathways to maintain Oct4, Sox2 and Nanog expression via Kruppel-like factor 4 (Klf4) and T-box factor 3 [184, 185]. Lif and IL-6 are necessary for STAT3 phosphorylation mediated by Jak1 [186]. Stat3 phosphorylation positively regulates Klf4 and Nanog transcripts and facilitates Lif-dependent maintenance of pluripotency in a signaling loop [106]. Stat3 directly binds to genomic sites of Oct4 and Nanog, regulates the Oct4-Nanog circuitry and is necessary to maintain the self-renewal and pluripotency of mESC [187-189]. Overexpression of Stat3 maintains mESC self-renewal even in the absence of Lif [190]. Withdrawal of LIF up-regulates the NFκB pathway and results in ESC differentiation as well as STAT3 disruption [191-193]. The interleukin 6 (IL-6) response element (IRE) is activated by STAT3, vice versa IL-6 stimulation leads to STAT3 phosphorylation and transactivation of IRE- containing promoters providing a positively regulated STAT3-IL6 loop. STAT3 directly associates with c-Jun and c-Fos in response to IL-6 [194]. c-Jun and c-Fos are DNA binding proteins and components of the AP-1 (activation protein-1) transcription factor complex [195]. AP-1 can be activated by TLR2/4, IL-10 or STAT3 to regulate inflammatory responses or drive keratinocyte differentiation in interplay with STAT3 and c-MYC [196]. Tlr2 also plays an important role in the maintenance of mESC [107]. STAT3 is important to tune appropriate amounts of AP-1 proteins required for proper differentiation. DNA binding sites for both AP-1 and STAT3 have been found in many gene promoters [194, 197]. It is important to note that c-Jun is able to capture or release the NuRD (nucleosome remodeling and deacetylation) repressor complex, an important epigenetic modulator of gene silencing [198, 199]. STAT3 is able to bind to bivalent histone modifications enabling a quick switch between the activation of pluripotency genes during ESC maintenance and their inhibition during cell differentiation [193].
STAT3 also has complex functions during hematopoietic development, immune regulation, cell growth, and leukemic transformation [200-202]. It is critically important for the survival and differentiation of lymphocytes and myeloid progenitors [171]. STAT3 signaling can be activated in a cell contact-dependent way, which is distinct from its cytokine activation. Co-cultures of MSC (human mesenchymal stem cells) and APC (antigen-presenting cell) increase STAT3 signaling in both cell types in a cell contact-dependent way, which mediates the immune-modulatory effects of MSC to block APC maturation and induce T-cell tolerance [203]. MSC are high-proliferative non-hematopoietic stem cells with the ability to differentiate into multiple mesenchymal lineages [204-206]. They accumulate in tumor environments in response to NFκB signaling and produce cytokines [207]. MSCs are FDA-approved for the treatment of severe acute GVHD, due to their immunomodulatory properties [208]. STAT3 phosphorylation is induced by cell-cell contacts and inhibited in postconfluent cells that consequently become apoptotic. Therefore, STAT3 may represent a molecular junction that allows cell proliferation or growth arrest depending on the state of the cell. Increased STAT3 activity may promote cell survival during cell confluency [209].
Constitutive STAT3 activation can by itself result in cellular transformation [210-214]. For example, contact-dependent STAT3 activation is known to play a promoting role in the interactions between tumor cells and their environment [215-218]. Cell transformation and the induction of pluripotency may share very similar signaling processes, and it is possible that STAT3 may represent a common axis [219, 220]. During early tumor development, certain cells have to acquire stem cell-like features that allow them to self-renew (tumor-initiating cells) and to produce cell progeny (tumor bulk) [221-224]. These tumor-initiating cells are very difficult to eradicate during chemotherapies and often re-establish the tumor seen as clinical relapse [225-227]. Tumor-initiating cells display strong inflammatory gene signatures with elevated IL6-STAT3-NFκB signaling to sustain their self-renewal [228-231]. A better understanding of the mechanism by which STAT3 and NFκB regulates the acquisition of pluripotency and self-renewal might also give us crucial insight about tumor development, and may lead to future novel therapies [171, 232].
Activation of Stat3 is a limiting factor for the induction of pluripotency, and its over-expression eliminates the requirement for additional factors to establish pluripotency [233]. These key properties have positioned Stat3 signaling as one of the master reprogramming factors that dominantly instructs naïve pluripotency [175]. Elevated Stat3 activity overcomes the pre-iPSC reprogramming block and enhances the establishment of pluripotency induced by SOKM [234]. Stat3 and Klf4 co-occupy genomic sites of Oct4, Sox2 and Nanog. Klf4 and c-Myc are downstream targets of Stat3 signaling and part of the transcriptional network governing pluripotency. The Stat3 effect is combinatorial with other reprogramming factors, which implies that additional targets of Stat3 play a pivotal role [235].
Stat3 activation regulates major epigenetic events that induce an open-chromatin state during late-stage reprogramming to establish pluripotency [236-238]. For example, Stat3 signaling stimulates DNA methylations to silence lineage commitment genes and facilitates DNA demethylations to activate pluripotency-related genes [106, 239, 240]. Other chromatin modifications include histone acetylation and deacetylation, which are catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activities. Histone acetylation is associated with an open chromatin state that allows active gene transcription. HDAC inhibitors are known to significantly improve the efficiency of iPSC generation by allowing promoter accessibility [128, 241, 242]. STAT3 suppresses HDAC expression and repressive chromatin regulators to establish an open-chromatin structure giving full access to transcriptional machineries. The key pluripotency factor Nanog cooperates with Stat3 to maintain ESC pluripotency [173]. Interestingly, HDAC inhibitors but not NANOG over-expression rescues complete reprogramming in the presence of STAT3 inhibition.
Finally, DNA demethylation is regulated in mammalian cells by Tet proteins (tet methylcytosine dioxygenase), which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet1 suppresses ESC differentiation and Tet1 knockdown leads to defects in ESC self-renewal. Tet1 up-regulation is positively regulated by Stat3 during the late-reprogramming stage [243-246].
The NFκB and STAT3 pathways are closely interconnected in regulating immune responses [247, 248]. STAT3 activation itself induces further STAT3 phosphorylation. Un-phosphorylated STAT3 that accumulates in the cell can bind to un-phosphorylated NFκB in competition with IκB. The resulting STAT3/NFκB dimer localizes to the nucleus to induce NFκB-dependent gene expression [249]. STAT3 associates with the p300/CBP (CREB-binding protein) co-activator enabling its histone acetyltranferase activity to open chromatin structures, which allows chromatin-modifying proteins to bind the DNA and activate gene transcription. [250, 251] Tyrosine-phosphorylated and acetylated STAT3 additionally binds to the NFκB precursor protein p100 and induces its processing to p52 by activation of IKKα. STAT3 then binds to the DNA-binding p52 complex to assist in the activation of target genes [252]. Both, the NFκB and STAT3 pathway synergize during terminal B-cell differentiation [253]. Phosho-p65/STAT3 dimers and phospho-STAT3/NFκB dimer complexes can bind to κB motifs. Also, phospho-STAT3 and phosho-p50 interact with each other. Soluble CD40L rapidly activates NFκB p65 and up-regulates IL10 receptors on the cell surface. This renders STAT3 more susceptible to IL-10 induced phosphorylation [161]. Macrophage activation is regulated by Toll-like receptors, JAK/STAT signaling and immunoreceptors that signal via ITAM motifs [254, 255]. These pathways have low activity levels under homeostatic conditions but are strongly activated during innate immune responses. ITAM-coupled receptors cooperate with TLRs in driving NFκB signaling and inflammation during infections, whereas extensive ITAM activation inhibits JAK/STAT signaling to limit the immune reaction [256, 257]. Pleiotropic cytokines like interferons and IL-6 regulate the balance of pro-and anti-inflammatory functions by activating variable levels of STAT1 and STAT3 [258].
NFκB and STAT3 are also part of an important stem cell pathway axis [259, 260]. A functional link between NANOG, NFκB and LIF/STAT3 signaling was shown in the maintenance of pluripotency [228]. Non-canonical NFκB signaling is activated by STAT3 through activation of IKKα and p100 processing [58]. Conversely, STAT3 inhibits TLR-induced canonical NFκB activity probably through up-regulated SOCS3. C-terminal binding of NANOG inhibits the pro-differentiation activities of canonical NFκB signaling and directly cooperates with STAT3 to maintain ESC pluripotency. NANOG and STAT3 bind to each other and synergistically activate STAT3-dependent promoters [106, 261].
The STAT3 pathway also interacts with many signaling pathways that are critically involved in the reprogramming process. For example, STAT3 signaling activates the MYC transcriptome and signals in loop with LIN28 [229]. LIN28 is expressed in undifferentiated hESC and is able to enhance the reprogramming efficiency of fibroblasts. It is down-regulated upon ESC differentiation [262-265]. Proto-oncogene tyrosine-protein kinase Src activation triggers an inflammatory response mediated by NFκB that directly activates IL6 and Lin28B expression through a binding site in the first intron. IL6-mediated activation of STAT3 transcription is necessary for monocyte activation and tumorigenesis. IL6 itself further activates NFκB, thereby completing a positive NFκB-STAT3-IL6 feedback loop that links inflammation to cell transformation [229]. Constitutive STAT3 signaling maintains constitutive NFκB activity in tumors by inhibiting its nuclear export through p65 acetylation, although STAT3 signaling inhibits NFκB activation during normal immune responses [52].
A panoply of chromatin remodelers play active, regulatory roles during the reprogramming process [266, 267]. For example, the Mbd3/NuRD complex is an important epigenetic regulator that restricts the expression of key pluripotency genes [268]. MBD3 (Methyl-CpG-binding domain protein 3) is part of the NuRD (nucleosome remodeling and deacetylation) repressor complex, which mediates chromatin remodeling through histone deacetylation via HDAC1/2 and ATPase activities [269-271]. The NuRD complex interacts with methylated DNA to mediate heterochromatin formation and transcriptional silencing of ESC-specific genes. Whereas MBD2 recruits NuRD to methylated DNA, MBD3 fails to bind methylated DNA as it evolved from a methyl-CpG-binding domain to a protein–protein interaction module [272]. Mbd3 antagonizes the establishment of pluripotency and facilitates differentiation [273].
Recent evidence suggested that efficient reprogramming may require NuRD complex down-regulation [274]. The reprogramming factors OCT4, SOX2, KLF4 and MYC bind to MBD3, a critical component of the NURD complex. In the absence of MBD3, SOKM over-expression induces pluripotency with almost 100% efficiency [275]. Such reprogramming occurs within seven days in mouse cells. Once pluripotency is established, MBD3 does not appear to compromise its maintenance. The MBD3/NuRD repressor complex is probably the predominant molecular block that prevents the induction of ground-state pluripotency. Several reprogramming factors directly interact with the MBD3/NuRD complex to form a potent negative regulatory complex that restrains pluripotency gene reactivation. Thus, chromatin de-repression is of critical importance for the conversion of somatic cells into iPSC.
Embryonic stem cells are not only able to maintain their undifferentiated state indefinitely, but also need to retain their ability to differentiate into various cell types [276]. The co-existence of these two features requires the combined action of signal transduction pathways, transcription factor networks, and epigenetic regulators [277]. Pluripotent gene expression has to be maintained in a way that it can be rapidly silenced upon receiving differentiation signals. The NuRD complex maintains this ESC flexibility by inducing variability in pluripotency factor expression that results in a low-expressing subpopulation of ESCs primed for differentiation [268, 278]. The control of gene expression by juxtaposition of antagonistic chromatin regulators is a common regulatory strategy in ESC, called bivalent histone modification [279, 280]. Individual promoters exhibit trimethylation of two different residues of histone H3: lysine 4 (H3K4me3) and lysine 27 (H3K27me3) [281, 282]. H3K27me3 is a repressive histone modification, whereas H3K4me3 is an activation-associated mark [283]. Both epigenetic markers have opposing effects and allow quick adjustments between ESC self-renewal and differentiation. Bivalent genes are generally transcriptionally silent in ESCs but are prone for rapid activation. MBD3 binding is enriched at bivalent genes characterized by 5hmC modifications. STAT3 binds to bivalent histone modifications and is able to switch between cellular pluripotency and differentiation [236, 284, 285].
MBD3 plays key roles in the biology of 5-hydroxy-methylcytosine (5hmC) [286]. 5hMC is an oxidation product of 5-methylcytosine (5mC) [287, 288]. MBD3 silences pluripotency genes like Oct4 and Nanog through 5-hydroxy-methylation of their promoters. MBD3 binds to 5hmC in cooperation with Tet1 to regulate 5hmC-marked genes, but does not interact with 5mC. Mbd3 interaction with 5hmC recruits NuRD to its targets resulting in gene repression. Knockdown of the MBD3/NuRD complex affects the expression of 5hmC-marked genes [289]. Mbd3 acts upstream of Nanog and may block the transition from partially to fully reprogrammed iPSC by silencing Nanog. Nanog overexpression was dominant over Mbd3 knockdown in the induction of efficient reprogramming and is in general sufficient to maintain mESC pluripotency. Mbd3 depletion facilitates the transcription of Oct4 and Nanog and leads to the generation of iPSC and chimeric mice even in the absence of Sox2 or c-Myc [290]. The depletion of Mbd3/NuRD does not replace Oct4 during iPSC formation as reprogramming did not occur with Klf4 and c-Myc alone. Mbd3-dependent silencing of pluripotency factors occurs during ESC differentiation. This involves NuRD-dependent deacetylation of H3K27 required for the binding of the polycomb repressive complex two. NuRD-dependent silencing of pluripotency genes prevents the de-differentiation of somatic cells. In the absence of Mbd3, NuRD disassembles, which lowers this epigenetic barrier and allows the activation of pluripotency genes. Drug-induced down-regulation of Mbd3/NuRD may greatly improve the efficiency and fidelity of reprogramming [291].
The master reprogramming factor STAT3 may overcome an unknown reprogramming block by inducing an open chromatin formation that facilitates the pluripotency factors SOKM to bind to ESC gene promoters. We hypothesize that upstream inflammatory signals mediated by NFκB signaling may facilitate STAT3 to de-repress the NuRD complex via c-Jun.
Stat3 promotes the expression of self-renewal transcription factors and opposes NURD-mediated repression of several hundred target genes in ESCs. The opposing functions of Stat3 and NuRD maintain variability in the levels of key self-renewal transcription factors. Stat3, but not NuRD, is the rate-limiting factor for pluripotency gene expression. Self-renewing ESC face a barrier that prohibits differentiation. NuRD constrains this barrier within a range that can be overcome when self-renewal signals are withdrawn [268, 278, 292]. Mbd3/NuRD-mediated gene silencing is a critical determinant of lineage commitment in embryonic stem cells and allows cells to exhibit pluripotency and self-renewal. Mbd3-deficient ESC show persistent self-renewal even in the absence of Lif. They are able to undergo the initial steps of differentiation, but their ability for lineage commitment is severely compromised. They fail to downregulate undifferentiated cell markers as well as upregulate differentiation markers [293]. Stat3 has many downstream effectors like the proto-oncogene c-Jun that is part of the AP-1 complex [194]. The transactivation domain of un-phosphorylated c-Jun recruits Mbd3/NuRD to AP-1 target genes to mediate gene repression. This repression is relieved by c-Jun N-terminal phosphorylation or Mbd3 depletion. Upon JNK activation, NuRD dissociates from c-Jun, which results in de-repression of target gene transcription. Termination of the JNK signal induces Mbd3/NuRD re-binding to un-phosphorylated c-Jun and cessation of target gene expression (Figure 2) [199].
In this review, we have discussed a potentially novel link between inflammatory pathways and efficient cell reprogramming. In this context, our group reported that bone marrow stromal-primed human myeloid cell progenitors are significantly more receptive to reprogramming stimuli than other cell types [20]. Myeloid cells harbor a unique epigenetic plasticity that allows them to quickly respond to a plethora of pathogens. They are innately equipped to transcriptionally and epigenetically activate key inflammatory pathways via an interconnected NFκB and STAT3 signaling machinery [294]. Both pathways act as epigenetic modifiers during normal inflammation stimulation, and both are also known to promote ESC pluripotency by inducing an open chromatin state that allows other transcription factors to regulate cell fates [236]. This epigenetic remodeling may prove crucial for efficient reprogramming, as well as the generation of high quality iPSC that resemble ESC without excessive epigenetic memory of their cell of origin [295].
Moreover, Stat3 is a master reprogramming factor that is able to dominantly instruct pluripotency, yet is also inherently interconnected with inflammatory signaling cascades (Figure 2). It binds to bivalent histone modifications, and allows rapid transitions between pluripotency and differentiation [193]. The NFκB pathway acts in synergy with downstream STAT3 signaling, whereby non-canonical NFκB signaling maintains pluripotency through epigenetic silencing of differentiation genes and canonical NFκB signaling promotes cell differentiation [296]. Finally, recent evidence suggests that strong chromatin repression by the NuRD complex is a key rate-limiting factor during reprogramming to pluripotency. This important complex may normally function to ensure that differentiated cells do not reactivate pluripotency genes, which might enable tumorigenesis [268]. We propose the hypothesis that NuRD complex silencing might be more easily achieved through the activation of inflammatory pathways in receptive cells such as those from the myeloid lineage.
It remains to be elucidated how all these processes are inter-regulated. It will be especially important to link reprogramming efficiency with the resulting quality of the pluripotent state achieved in hiPSC. We hypothesize that epigenetic plasticity in inflammatory cells that normally allows chromatin accessibility to the transcriptional machinery, could be manipulated to facilitate a complete erasure of the donor epigenetic memory during factor-mediated reprogramming. Additionally, preventing cancerous epigenetic patterns in iPSC via more accurate high-fidelity reprogramming methods will be the foundation for future clinical applications [13]. Finally, the basic understanding of pluripotency induction may also give us a better understanding of how tumor-initiating cells arise and how they can be eradicated to prevent tumor relapse, thus potentially opening a new era of cancer treatments.
JRA was supported by a fellowship from the German Research Foundation (DFG, DJ 71/1-1). ETZ was supported by grants from the NIH/NHLBI U01HL099775 and the Maryland Stem Cell Research Fund (2011-MSCRF-II-0008-00; 2007-MSCRF-II-0379-00). We would like to thank Dr. Alan Friedman for assistance in reading and editing the manuscript.
There may not be a precise background to the first discovery and application of phase change materials (PCMs). Perhaps, from the earliest days where human has acquired the intellect, he has realized the existence of these substances or, maybe, has used them without recognizing their nature. Throughout science and technology evolution, more precisely, since the heat capacity of materials and sensible or latent heats have been known, their ability to store and release thermal energy has also been considered. However, A. T. Waterman submitted the first report of discovery in the early 1900s. In recent years, scientists have paid particular attention to these materials, and their commercialization began from those years.
Perhaps the main reason for this attention was the problems caused by energy mismanagement and improper use of it. Today, inadequate energy management, especially fossil fuels, has caused many environmental and economic problems. Therefore, the necessity of efficient energy demand as well as development of renewable energies and energy storage systems is highly significant. One of the important topics in this field is the design of special energy storage equipment to other types. Energy storage not only reduces the discrepancy between energy supply and demand but also indirectly improves the performance of energy generation systems as well as plays a vital role in saving of energy by converting it into other reliable forms. Hence, this matter saves high-quality fuels and reduces energy wastes [1, 2, 3].
Energy storage is one of the important parts of renewable energies. Energy can be stored in several ways such as mechanical (e.g., compressed air, flywheel, etc.), electrical (e.g., double-layer capacitors), electrochemical (e.g., batteries), chemical (e.g., fuels), and thermal energy storages [4].
Among several methods of energy storage, thermal energy storage (TES) is very crucial due to its advantages. TES is accomplished by changing the internal energy of materials, such as sensible heat, chemical heat, latent heat, or a combination of them.
In sensible heat storage (SHS) systems, heat can be stored by increasing the temperature of a material. Hence, this system exploits both the temperature changes and the heat capacity of the material to store energy. The amount of heat stored in this system depends on the specific heat, temperature differences, and amount of material; thus it requires a large amount of materials, whereas Latent heat storage (LHS) is generally based on the amount of heat absorbed or released during the phase transformation of a material. Lastly, In the chemical heat storage (CHS), heat is stored by enthalpy change of a chemical reaction.
Among the aforementioned heat storage systems, the LHS is particularly noteworthy. One of the special reasons is its ability to store large amount of energy at an isothermal process [5, 6, 7].
Any high-performance LHS system should contain at least one of the following terms:
Appropriate PCM with optimum melting temperature range
Desirable and sufficient surface area proportional to the amount of heat exchange
Optimal capacity compatible with PCM
Phase change materials perform energy storage in LHS method. In this case, a material during the phase change absorbs thermal energy from surrounding to change its state, and in the reverse process, the stored energy is released to the surrounding. PCMs initially behave likewise to other conventional materials as the temperature increases, but energy is absorbed when the material receives heat at higher temperatures and close to the phase transformation. Unlike conventional materials, in PCMs absorption or release of thermal energy is performed at a constant temperature. A PCM normally absorbs and releases thermal energy 5–14 times more than other storage materials such as water or rock [8, 9].
PCMs can store thermal energy in one of the following phase transformation methods: solid-solid, solid-liquid, solid-gas, and liquid-gas. In the solid-solid phase change, a certain solid material absorbs heat by changing a crystalline, semicrystalline, or amorphous structure to another solid structure and vice versa [10]. This type of phase change, usually called phase transitions, generally has less latent heat and smaller volume change comparing to the other types. Recently, this type of PCM has been used in nonvolatile memories [11].
Solid-liquid phase change is a common type of commercial PCMs. This type of PCM absorbs thermal energy to change its crystalline molecular arrangement to a disordered one when the temperature reaches the melting point. Unlike solid-solid, solid-liquid PCMs contain higher latent heat and sensible volumetric change. Solid-gas and liquid-gas phase changes contain higher latent heat, but their phase changes are associated with large volumetric changes, which cause many problems in TES systems [8]. Although the latent heat of solid-liquid is less than liquid-gas, their volumetric change is much lower (about 10% or less). Therefore, employing PCMs based on solid-liquid phase change in TES systems would be more economically feasible.
The overall classification of energy storage systems as well as phase change materials is given in Figure 1.
Overview of energy storage and classification of phase change materials.
As mentioned in the previous section, despite the high thermal energy absorption capacity, PCMs in liquid-gas and solid-gas transitions have extremely high volume changes. On the other hand, solid-solid PCMs also have a lower thermal energy storage capacity. Therefore, the abovementioned PCMs, with the exception of specific cases, have not received much attention to commercialization. Currently, the most common type of transition that has been mass-marketed is solid-liquid PCMs. The classification of phase change materials is schematically given in Figure 1. Solid-liquid PCMs are generally classified as three general organics, inorganic, and eutectics [12, 13]. However, in some references they are classified into two major organics and inorganics.
Inorganic PCMs mainly have high capacity for thermal energy storage (about twice as much as organic PCMs) as well as have higher thermal conductivity. They are often classified as salt hydrates and metals.
Salt hydrates are the most important group of inorganic PCMs, which is widely employed for the latent heat energy storage systems. Salt hydrates are described as a mixture of inorganic salts and water (AB × nH2O). The phase change in salt hydrates actually involves the loss of all or plenty of their water, which is roughly equivalent to the thermodynamic process of melting in other materials.
At the phase transition, the hydrate crystals are subdivided into anhydrous (or less aqueous) salt and water. Although salt hydrates have several advantages, some deficiencies make restrictions in their application. One of these problems is incongruent melting behavior of salt hydrates. In this problem the released water from dehydration process is not sufficient for the complete dissolution of the salts. In this case, the salts precipitate and as a result phase separation occurs. In order to prevent this problem, an additional material such as thickener agent is added to salt hydrates. Another major problem with salt hydrates is the supercooling phenomenon. In this phenomenon, when crystallization process occurs, the nucleus formation is delayed; therefore, even at temperatures below freezing, the material remains liquid [7, 11, 14].
Overall, the most attractive properties of salt hydrate are (i) high alloy latent temperature, (ii) relatively high thermal conductivity (almost two to five times more than paraffin), and (iii) small volume changes in melting. They are also very low emitting and toxic, adaptable to plastic packaging, and cheap enough to use [15].
Metalsare another part of the inorganic PCMs. Perhaps the most prominent advantages of metals are their high thermal conductivity and high mechanical properties. Metals are available over a wide range of melting temperatures. They are also used as high-temperature PCMs.
Some metals such as indium, cesium, gallium, etc. are used for low-temperature PCMs, while others such as Zn, Mg, Al, etc. are used for high temperatures. Some metal alloys with high melting points (in the range of 400–1000°C) have been used for extremely high temperature systems. These metal alloys as high-temperature PCMs can be used in the field of solar power systems [16, 17]. They can also be used in industries that require temperature regulation in furnaces or reactors with high operating temperatures.
Perhaps the most important fragment is the organic PCMs. Organic PCMs show no change in performance or structure (e.g., phase separation) over numerous phase change cycles. In addition, supercooling phenomena cannot be observed in organic PCMs. The classification of organic PCMs is unique. This division is mainly based on their application contexts. In general, they are classified into two major paraffin and non-paraffin sections.
Paraffins are the most common PCMs. Since this book is about paraffin, to avoid duplication, this section will briefly discuss the chemistry (structure and properties) of paraffin, but their ability as phase change materials will be reviewed in detail.
Non-paraffinic organic PCMs are known to be the most widely used families. In addition to their different properties compared to paraffins, they have very similar properties to each other. Researchers have used various types of ether, fatty acid, alcohol, and glycol as thermal energy storage materials. These materials are generally flammable and less resistant to oxidation [18, 19, 20].
Although non-paraffin organic PCMs have high latent heat capacity, they have weaknesses such as flammability, low thermal conductivity, low combustion temperatures, and transient toxicity. The most important non-paraffinic PCMs are fatty acids, glycols, polyalcohols, and sugar alcohols.
Fatty acids [CH3(CH2)2nCOOH] also have high latent heat. They can be used in combination with paraffin. Fatty acids exhibit high stability to deformation and phase separations for many cycles and also crystallize without supercooling. Their main disadvantages are their costs. They are 2–2.5 times more expensive than technical grade paraffins. Unlike paraffins, fatty acids are of animal or plant origin. Their properties are similar to those of paraffins, but the melting process is slower. On the other hand, they are moderately corrosive as well as generally odorous [21].
A eutectic contains at least two types of phase change materials. Eutectics have exceptional properties. In eutectics, the melting-solidification temperatures are generally lower than the constituents and do not separate into the components through the phase change. Therefore, phase separation and supercooling phenomena are not observed in these materials.
Eutectics typically have a high thermal cycle than salt hydrates. Inorganic-inorganic eutectics are the most common type of them. However, in recent studies, organic-inorganic and organic-organic varieties have received more attention. The major problem of eutectics is their commercialization. Their cost is usually two to three times higher than commercial PCMs [22, 23].
Some of the above PCMs and their thermal properties, which are competitive with paraffins in terms of latent heat capacity, are summarized in Table 1.
Type of PCMs | Materials | Melting point (°C) | Latent heat (kJ/kg) | Density* (kg/m3) | Thermal conductivity (W/mK)** | Ref. | |
---|---|---|---|---|---|---|---|
Inorganic salt hydrates | LiClO3·3H2O | 8 | 253 | 1720 | [24, 25] | ||
K2HPO4·6H2O | 14 | 109 | [24] | ||||
Mn(NO3)2·6H2O | 25.8 | 126 | 1600 | [14, 25] | |||
CaCl2·6H2O | 29.8 | 191 | 1802 | 1.08 | [24, 25] | ||
Na2CO3·10H2O | 32–34 | 246–267 | [14, 24] | ||||
Na2SO4·10H2O | 32.4 | 248, 254 | 1490 | 0.544 | [14, 26] | ||
Na2HPO4·12H2O | 34–35 | 280 | 1522 | 0.514 | [15, 26] | ||
FeCl3·6H2O | 36–37 | 200, 226 | 1820 | [25, 26] | |||
Na2S2O3·5H2O | 48–49 | 200, 220 | 1600 | 1.46 | [15, 26] | ||
CH3COONa·3H2O | 58 | 226, 265 | 1450 | 1.97 | [15, 26] | ||
Non-paraffinic organic PCMs | Fatty acids | Formic acid | 8.3 | 247 | 1220 | — | [1, 25] |
n-Octanoic acid | 16 | 149 | 910 | 0.148 | [21, 27] | ||
Lauric acid | 43.6 | 184.4 | 867 | [21, 25] | |||
Palmitic acid | 61.3 | 198 | 989 | 0.162 | [21, 27] | ||
Stearic acid | 66.8 | 259 | 965 | 0.172 | [21, 25] | ||
Polyalcohols | Glycerin | 18 | 199 | 1250 | 0.285 | [1, 25] | |
PEG E600 | 22 | 127.2 | 1126 | 0.189 | [27] | ||
PEG E6000 | 66 | 190 | 1212 | [27] | |||
Xylitol | 95 | 236 | 1520 | 0.40 | [28] | ||
Erythritol | 119 | 338 | 1361 | 0.38 | [28] | ||
Others | 2-Pentadecanone | 39 | 241 | [1, 25] | |||
4-Heptadekanon | 41 | 197 | [1, 25] | ||||
D-Lactic acid | 52–54 | 126, 185 | 1220 | [1, 25] | |||
Eutectics | O-O, O-I, I-I *** | CaCl2·6H2O + MgCl2·6H2O | 25 | 127 | 1590 | [27] | |
Mg(NO3)2·6H2O + MgCl2·6H2O | 59 | 144 | 1630 | 0.51 | [27] | ||
Trimethylolethane + urea | 29.8 | 218 | [21] | ||||
CH3COONa·3H2O + Urea (60:40) | 31 | 226 | [27] | ||||
Metals | Mg-Zn (72:28) | 342 | 155 | 2850 | 67 | [16, 17] | |
Al-Mg-Zn (60:34:6) | 450 | 329 | 2380 | [16, 17] | |||
Al-Cu (82:18) | 550 | 318 | 3170 | [16, 17] | |||
Al-Si (87.8:12.2) | 580 | 499 | 2620 | [16, 17] |
Thermophysical properties of some common PCMs with high latent heat.
At 20°C.
Just above melting point (liquid phase).
Inorganic-inorganic (I-I), organic-inorganic (O-I), and organic-organic (O-O).
Paraffin is usually a mixture of straight-chain n-alkanes with the general formula CH3-(CH2)n-CH3. However, in some cases, paraffin is used as another name for alkanes. Gulfam R. et al. in their article have classified paraffins based on the number of carbon atoms as well as their physical states. According to this classification, at room temperature, 1–4 numbers of carbons refer to pure alkanes in a gas phase, 5–17 carbons are liquid paraffins, and more than 17 is known as solid waxes. These waxy solids refer to a mixture of saturated hydrocarbons such as linear, iso, high branched, and cycloalkanes [29]. Generally, paraffin-based PCMs are known as waxy solid paraffins. Commercial paraffins contain mixture of isomers, and therefore, they have a range of melting temperatures.
Paraffins typically have high latent heat capacity. If the length of the chain increases, the melting ranges of waxes also increase, while the latent heat capacity of melting is not subject to any particular order (Table 2).
Materials | Melting point (°C) | Latent heat (kJ/kg) | Density* (kg/m3) | Thermal conductivity** (W/mK) |
---|---|---|---|---|
n-Tetradecane (C14) | 6 | 228–230 | 763 | 0.14 |
n-Pentadecane (C15) | 10 | 205 | 770 | 0.2 |
n-Hexadecane (C16) | 18 | 237 | 770 | 0.2 |
n-Heptadecane (C17) | 22 | 213 | 760 | 0145 |
n-Octadecane (C18) | 28 | 245 | 865 | 0.148 |
n-Nonadecane (C19) | 32 | 222 | 830 | 0.22 |
n-Eicosane (C20) | 37 | 246 | ||
n-Henicosane (C21) | 40 | 200, 213 | 778 | |
n-Docosane (C22) | 44.5 | 249 | 880 | 0.2 |
n-Tricosane (C23) | 47.5 | 232 | ||
n-Tetracosane (C24) | 52 | 255 | ||
n-Pentacosane (C25) | 54 | 238 | ||
n-Hexacosane (C26) | 56.5 | 256 | ||
n-Heptacosane (C27) | 59 | 236 | ||
n-Octacosane (C28) | 64.5 | 253 | ||
n-Nonacosane (C29) | 65 | 240 | ||
n-Triacontane (C30) | 66 | 251 | ||
n-Hentriacontane (C31) | 67 | 242 | ||
n-Dotriacontane (C32) | 69 | 170 | ||
n-Triatriacontane (C33) | 71 | 268 | 880 | 0.2 |
Paraffin C16-C18 | 20–22 | 152 | ||
Paraffin C13-C24 | 22–24 | 189 | 900 | 0.21 |
RT 35 HC | 35 | 240 | 880 | 0.2 |
Paraffin C16-C28 | 42–44 | 189 | 910 | |
Paraffin C20-C33 | 48–50 | 189 | 912 | |
Paraffin C22-C45 | 58–60 | 189 | 920 | 0.2 |
Paraffin C21-C50 | 66–68 | 189 | 930 | |
RT 70 HC | 69–71 | 260 | 880 | 0.2 |
Paraffin natural wax 811 | 82–86 | 85 | 0.72 (solid) | |
Paraffin natural wax 106 | 101–108 | 80 | 0.65 (solid) |
In general, paraffin waxes are safe, reliable, inexpensive, and non-irritating substances, relatively obtained in a wide range of temperatures. As far as economic issues are concerned, most technical grade waxes can be used as PCMs in latent heat storage systems. From the chemical point of view, paraffin waxes are inactive and stable. They exhibit moderate volume changes (10–20%) during melting but have low vapor pressure.
The paraffin-based PCMs usually have high stability for very long crystallization-melting cycles. Table 2 illustrates the thermal properties of some paraffin waxes.
Besides the favorable properties, paraffins also show some undesirable properties such as low thermal conductivity, low melting temperatures, and moderate-high flammability. Some of these disadvantages especially thermal conductivity and flammability can be partially eliminated with the help of additives or paraffin composites.
Measures must be taken to make the solid-liquid PCMs usable. For this purpose, there are several methods for stabilizing the shapes of paraffinic PCMs. Two main methods of them are discussed below.
Encapsulation is generally a worthy method to protect and prevent leakage of PCMs in the liquid state. The capsules consist of two parts, the shell and the core. The core part contains PCMs, whereas the shell part is usually composed of polymeric materials with improved mechanical and thermal properties. The shell part plays the role of protection, heat transfer, and sometimes preventing the release of toxic materials into the environment. In these cases, the shell must have appropriate thermal conductivity. Polymeric shells are also commonly used in encapsulating PPCMs. The choice of core part depends on its application field. The encapsulation of PPCMs is classified into three major parts: bulk or macroencapsulation, microencapsulation, and nano-encapsulation.
Macroencapsulation is one of the simplest ways to encapsulate paraffins. This method has a lower cost than other methods. These products are used in transportation, buildings, solar energy storage systems, and heat exchangers. Sometimes metals are also used as shell materials [30].
In order to increase the efficiency of heat transfer in these types of capsules, either the size of the capsules should be appropriately selected or suitable modifiers should be used. In general, the smaller the diameter of spherical capsules or cylinders, the better the heat transfer. In some cases, metal foams are used to improve the heat transfer properties of paraffin. Aluminum and copper open-cell foams are among the most studied, whereas, in other cases metal oxides, metals and graphite are used [30, 31].
There are various forms of macroencapsulation, such as ball shape, spherical shape, cylindrical, flat sheets, tubular, etc. [31]. Cylindrical tubes are one of the famous forms of macroencapsulated PPCMs. This type of encapsulation is most commonly used in buildings or in solar energy storage systems.
Most of the research carried out on macroencapsulated PPCMs has been focused on improving their thermal conductivity. In one of these studies, different metal oxide nanoparticles such as aluminum oxide, titanium oxide, silicon oxide, and zinc oxide were used to improve the thermal conductivity of paraffin. The results show that titanium oxide performs better under the same conditions than the other oxides [32]. In a similar study, copper oxide nanoparticles were used to improve thermal conductivity and performance of paraffin in solar energy storage systems [33]. In some studies, graphite flakes and expanded graphite have also been used as improving agent for heat conductivity [31].
Hong et al. have used polyethylene terephthalate pipes as a shell for paraffin. In this macroencapsulated system, introduced as cylinder modules, float stone has been added to paraffin as an enhancer of thermal conductivity. In this study, the effect of various parameters such as pipe diameter on heat transfer is investigated, and the results of experimental section are compared with modeling [34].
D. Etansova et al. studied numerical computation and heat transfer modeling of paraffin-embedded stainless steel macroencapsulates for use in solar energy storage systems. In this study, the effect of geometric size and shape on heat transfer was investigated [35].
Microencapsulation of PCMs is another suitable way to improve efficiency and increase thermal conductivity. The size of the microencapsulates usually ranges from 1 μm to 1 mm. Microencapsulation of paraffins is a relatively difficult process, but it performs better than macroencapsulates. This is due to increased contact surface area, shorter discharge and loading times, and improved thermal conductivity. Different materials are used for the shell part of the microencapsulates.
In general, there are two major physical and chemical methods for microencapsulation. The most important physical methods are fluidized bed, spray dryer, centrifuge extruder, and similar processes. However, chemical methods are often based on polymerization. The most important techniques include in situ suspension and emulsion polymerization, interfacial condensation polymerization, and sol-gel method. The latter is sometimes known as the physicochemical method [12, 29].
In the suspension or emulsion polymerization method, the insoluble paraffin is first emulsified or suspended in a polar medium, which is predominantly aqueous phase, by means of high-speed stirring. Surfactants are used to stabilize the particles. Then, lipophilic monomers are added to the medium, and the conditions are prepared for polymerization. This polymer, which is insoluble in both aqueous and paraffin phases, is formed on the outer surface of paraffin particles and finally, after polymerization, encapsulates the paraffin as a shell. The size of these capsules depends on the size of emulsion or suspension of paraffin droplets. Sometimes certain additives are added to the medium to improve some of the polymer properties. For instance, in some studies, polyvinyl alcohol (PVA) has been added to the medium with methyl-methacrylate monomer, which is known as one of the most important shell materials. As a result, paraffin has been encapsulated by PVA modified polymethyl methacrylate (PMMA). Adding this modifier forms a smooth surface of the microencapsulates [36, 37].
In the interfacial method, soluble monomers in the organic phase with other monomers in the aqueous phase at the droplet interface form a polymer that precipitates on the outer layer of the organic phase.
The sol-gel method is a multi-step procedure. In this method, firstly, an organosilicon compound such as tetraethoxysilane (TEOS) is hydrolyzed in an acidic medium at low pH. The prepared homogenous solution is known as the sol part. Then, the paraffin emulsion is prepared in an aqueous medium and stabilized by special emulsifiers. Actually, these emulsifiers are the first layer of the shell. Subsequently, the sol solution is slowly added to the aqueous phase containing paraffin. The silicon compounds containing OH groups (silanols) form hydrogen bonding with polar side of emulsifiers, and finally the condensation process is carried out on the first layer interface. As a result, paraffin microencapsulates with an inorganic material that is often silica. Silica is one of the significant materials used as a shell for micro and nano-encapsulation. Silica has high thermal conductivity and on the other hand has better mechanical properties than some polymers [38, 39, 40, 41].
As mentioned, most of the materials used to microencapsulation are polymers. The main polymers used as shell materials are polymethyl methacrylate [42], polystyrene [43], urea-formaldehyde [44], urea-melamine-formaldehyde [45], polyaniline [46], etc. However, in many cases, these polymers are used in modified form. For example, polymethyl methacrylate modified with polyvinyl alcohol or with other methacrylates [36, 37], polystyrene copolymers [47], and melamine modified-formaldehyde with methanol [48] can be considered. Table 3 shows the most common polymers used as shell materials.
Core material PPCM | Shell material | Encapsulation method | Particle size (μm) | Recommended application | Ref |
---|---|---|---|---|---|
n-Nonadecane | Polymethyl methacrylate | Emulsion | ~ 8 | Smart building and textiles | [42] |
n-Heptadecane | Polystyrene | Emulsion | <2 | General fields | [43] |
Commercial paraffin wax | Polystyrene-co-PMMA | Suspension | ~ 20 | [50] | |
Commercial RT21 | PMMA | Suspension | 20–40 | [36] | |
Commercial RT21 | PMMA modified with PVA | Emulsion | 15 | Building | [37] |
Commercial paraffin wax | Polyaniline | Emulsion | <1 | [46] | |
Commercial paraffin wax | Urea-formaldehyde | In situ | ~ 20 | [44] | |
n-Octadecane, n-nonadecane | Urea-melamine-formaldehyde | In situ | 0.3-0.6 | [45] | |
Commercial paraffin wax | Methanol-melamine-formaldehyde | In situ | 10–30 | Building | [48] |
Commercial paraffin wax | Silica | Sol-gel | 4–10 | Textile | [38] |
Commercial paraffin wax | Silica | Sol-gel | 0.2–0.5 | [39] | |
n-Octadecane | Silica | Sol-gel | 7–16 | [40] | |
n-Pentadecane | Silica | Sol-gel | 4–8 | [41] |
Common materials for microencapsulation of PPCMs.
In addition to the aforementioned microencapsulation approaches, which mainly form polymeric materials as shells, other materials have been also recommended. For example, Singh and colleagues have used silver metal as a shell for paraffin microencapsulates. They first emulsified paraffin into small particles in water and then converted silver salts to metallic silver via an in situ reduction reaction. The average particle size of 329 μm has been reported, and the thermal properties of paraffin have been investigated using DSC and TGA. This type of metal shell microencapsulates has been suggested for use in microelectronics heat management systems [49].
There are several techniques to study the properties of micro and nano-encapsulates. In all studies, differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) have been used to determine the thermal properties of PPCMs, such as enthalpy of fusion, melting temperature, weight loss, degradation, etc. Various methods such as XRD, FTIR, and 12C NMR have been used to study the structure and chemical composition of PPCMs. The morphology and diameters of the microcapsules have often been studied by scanning electron microscopy (SEM) and particle size analyzer.
The latter technique is used to study the influence of different variables on the diameter of the microcapsules. One of these variables is the effect of stirring speed on emulsification of paraffin. The results of some studies show that higher stirring speed of emulsification process leads to decrease of the mean size of paraffin droplets [48].
Along with studies on the type of microcapsules, many studies have been conducted to improve thermal conductivity and mechanical properties of microencapsulates. Part of these studies has been dedicated to the effect of graphene and graphene oxide on the improvement of thermal conductivity [51]. L. Zhang et al. investigated the effect of graphene oxide on improving the mechanical properties and leakage protection as well as improving the thermal conductivity of melamine-formaldehyde as shell materials of PPCM microencapsulates [52]. In another part of studies, metals and metal oxides have been used. For example, 10 and 20 wt% of nanomagnetite (Fe3O4) with particle size from 40 to 75 nm increase the thermal conductivity by 48 and 60%, respectively [53]. Also, addition of TiO2 and Al2O3 nanoparticles in a mass fraction of 5% with respect to PPCM at the size range of 30–60 nm increases the thermal conductivity by 40 and 65%, respectively [54].
Nano-encapsulation of PPCM is very similar to the microencapsulation process. However, these types of encapsulation specific techniques, such as ultrasonic, are used to adjust the size of the paraffin droplets to less than 1 micron. In the next step, using the chemical methods mentioned in the microencapsulation method, the shell formation is performed. The most common method for nano-encapsulation is the emulsion polymerization method. However, although limited, interfacial and sol-gel methods have also been reported.
In recent years, research on polymeric matrix-based shape-stable PCMs has gained great importance. Among these types of phase change materials, the paraffin-polymer composite is particularly attractive. The combination of paraffin and polymers as new PCMs with a unique controllable structure can be widely used. This compound remains solid at paraffin melting point and even above without any softening, which is why this type of PCM is called shape-stable. These materials are well formed and have high-energy absorption capacity; hence they can be widely used as stable PCMs with specific properties. On the other hand, some problems such as high cost and difficulty of encapsulating processes could be resolved. Despite these advantages, some common disadvantages such as low thermal stability, low thermal conductivity, and relatively high flammability can restrict their application, particularly in building materials. For this reason, further studies are required to eliminate these disadvantages and improve the properties of these materials. A large part of research is relevant to increase or improve their thermal conductivity, flame retardation, and thermophysical and mechanical properties. Suitable additives are proposed to improve these properties [55, 56].
In some articles, a simple method involves mixing-melting of polyethylene and paraffin, consequently cooling the composite, or using a simple twin extruder to prepare a shape-stable PCM has been reported [57, 58]. When this compound contains sufficient polymer, a homogeneous mixture remains solid at temperatures above the melting point of paraffin and below the polymer melting point. During the preparation of these composites, no chemical reaction or chemical bonds are formed between the polymers and paraffin; therefore these types of compounds are considered as physical mixtures. Shape-stable PPCMs can be used in all previously described areas. Due to the thermoplastic properties of these composites, it is possible to melt and crystalize them for many cycle numbers. Shape-stable PPCMs have several advantages over other PCMs. They are also nontoxic and do not require high-energy consumption during production process.
Inaba and Tu [59] developed a new type of shape-stable PPCM and determined their thermophysical properties. These materials can be used without encapsulation. Feldman et al. [60] prepared plates of shape-stable PCM and determined their high thermal energy storage capacity when used in small chambers. In this type of polymer-based plates, fatty acids are used as PCMs that absorb or releases large amounts of heat during melting and solidification, without altering the composition of the shape-stable PCM. The same researchers determined the role of polymer-PCM sheets in stabilizing the shape and size of the plates when PCM was liquefied. The composition of paraffin and high-density polyethylene (HDPE) has been studied by Lee and Choi [61] and has been introduced as a shape-stable energy storage material. In this study, the amount of energy stored by the mentioned composites is also studied. They also studied the morphology of the high-density polyethylene crystal lattice (HDPE) and its effect on paraffin through scanning electron microscopy and optical microscopy (OM) analysis. On the other hand, they also reported of high thermal energy storage capacity of the prepared paraffin/HDPE-based shape-stable PCMs. Hong and Xin-Shi [62] synthesized polyethylene-paraffin as a shape-stable PCM and characterized its morphology and structure by scanning electron microscopy and its latent heat of melting by differential scanning calorimetry. In this study, a composition consisting of 75% paraffin as a cheap, effective, easy-to-prepare, low-temperature shape-stable PPCM is recommended. In another study, Xiao et al. [63] prepared a shape-stable PCM based on the composition of paraffin with a thermoplastic elastomer (styrene butadiene rubber) and determined its thermal properties. The obtained results show that the stable mixture has the phase changing property and the amount of latent heat of melting stored in this compound is estimated to be 80% of pure paraffin. In another part of this study, the thermal conductivity of PCMs was significantly increased by using graphite.
Despite the above benefits, some disadvantages of shape-stable PPCMs are also reported. One of the major problems is the softening and paraffin leakage phenomenon at elevated temperatures. Seiler partly resolved this problem by adding a different ratio of silica and copolymers to the polyethylene-paraffin composition [64]. Another problem is the low thermal conductivity of the polyethylene-paraffin compound. A lot of research has been conducted to increase this property. A. Sari [65] prepared two types of paraffin with different melting temperatures (42–44°C and 56–58°C) and combined each with HDPE as phase modifier. By addition of 3% expanded graphite, the thermal conductivity of composites increased by 14 and 24%, respectively. Zhang et al. [66] developed new PCMS based on graphite and paraffin with high thermal energy storage capacity and high thermal conductivity. Zhang and Ding et al. [67] have used various additives such as diatomite, Wollastonite, organic modified bentonite, calcium carbonate, and graphite to improve the thermal conductivity of shape-stable PCMs.
It should be noted that metal particles and metal oxides due to their higher thermal conductivity are widely used to improve this property of PCMs. One of the materials that has received more attention in recent years is alumina. Aluminum oxide nanoparticles were added to paraffin to increase its thermal conductivity in both liquid and solid states [57, 68]. This compound coupled with its high thermal conductivity is cheaper and more abundant than other metal oxides.
Another problem with shape-stable PPCMs is their flammability. The effect of various additives has been studied by scientists to eliminate this problem. One of the most effective of these substances is halogenated compounds, but they cause environmental pollution and also release toxic compounds while burning. Researchers have used hybrid and environmentally friendly materials to enhance the durability of flame retardant materials. They studied the effect of clay nanoparticles and organo-modified montmorillonite. Adding these materials not only increases their resistance to burning but also increases their mechanical and thermal properties [69, 70, 71]. In another study, Y. Cai et al. added paraffin, HDPE, and graphite, then added ammonium polyphosphate and zinc borate separately, and studied their resistance to burning. The results show that the addition of ammonium polyphosphate decreases flammability, while zinc borate increases the flammability risk [72]. One of the most interesting and harmless fire retardant compounds is metal hydroxides, especially aluminum hydroxide, magnesium hydroxide, or their combination [73, 74, 75].
Some researchers have used other advanced materials as supporting materials to prepare shape-stable PPCMs instead of using the polymer matrix [76, 77, 78]. Rawi et al. used acid-treated multi-walled carbon nanotubes (A-CNT). They reported that adding 5% by weight A-CNT to paraffin decreases 25% of the latent heat while increasing heat conductivity up to 84% [79]. Y. Wan et al. used pinecone biochar as the supporting matrix for PCMs. They prepared shape-stable PCM materials at different ratios and studied the leakage behavior. The optimal ratio is suggested as 60% of the PCM. For the above ratio, no PCM leakage was observed after the melting temperature. The results showed that the thermal conductivity of the same ratio shape-stable PCM increased by 44% compared to the pure PCM [80].
PCMs are available in a wide range of desired temperature ranges. Obviously, a PCM may not have all the properties required to store heat energy as an ideal material. Therefore, it would be more appropriate to use these materials in combination with either other PCMs or various additives to achieve the required features. However, as latent heat storage materials, while using PCMs, the thermodynamic, kinetic, and chemical properties as well as the economic and availability issues of them must be taken into account. Employed PCMs must have the optimum phase change temperature. On the other hand, the higher the latent heat of the material, the lower its physical size. High thermal conductivity also helps to save and release energy. From the physical and kinetic point of view, the phase stability of PCMs during melting and crystallization contributes to optimum thermal energy storage. Their high density also enables high storage at smaller material sizes. During phase change, smaller volume changes and lower vapor pressures are appropriate for continuous applications.
H. Nazir et al. in their review article [12] have explained the criteria for selection of PCMs as a pyramid. In this pyramid, at the bottom, known as the fundamentals, there are several items such as cost, regularity compliance, and safety. In the next section, the thermophysical properties such as energy storage capacity and runtime are discussed. In the upper section, reliability and operating environment consist of degradation, cycle life, shelf life, and thermal limits are reflected. Finally, at the top section of pyramid, user perception and convenience are located. These criteria help us to find a proper PCM for certain application fields.
These criteria may also be extended to paraffinic PCMs. Nowadays, paraffinic PCMs (PPCMs) are widely used as thermal energy storage materials, including solar energy storage systems, food industries, medical fields, electrical equipment protection, vehicles, buildings, automotive industries, etc. [24, 29, 81, 82, 83, 84, 85].
Generally, application fields of PPCMs can be considered in two main sections: thermal protection and energy storage purposes. The major difference between these two areas of application is in thermal conductivity of the PPCMs.
Protection and transportation of temperature-sensitive materials is one the mentioned area. Sometimes a certain temperature is required to transport sensitive medicines, medical equipment, food, etc. In all cases, using of PPCMs would be appropriate as they can regulate and stabilize the temperature over a given range. Similarly, in sensitive electrical equipment, these materials are also essential to prevent the maximum operating temperature. On the other hand, they can be used to prevent possible engine damage at high temperatures [86, 87].
One of the studies related to these issues is the use of paraffin containing heavy alkanes to protect electronic devices against overheating. In this study, paraffin has been used as a protective coating for the resistor chip, and its effect on cooling of the devices has been investigated. Experimental results show that paraffin coating increases the relative duration of overheating by 50 to 150% over the temperature range of 110–140°C [88]. In another study, a mixture of paraffin and polypropylene has been used as an overheating protector in solar thermal collectors [89].
However, energy storage purposes are the most important part of PPCM application. In general, PCMs act as passive elements and therefore do not require any additional energy source. Most studies on the application of energy storage properties of PPCMs have been confined to buildings, textiles, and solar systems. In the following, building applications will be further attended.
One of the main drawbacks of lightweight building materials is their low thermal storage capacity, which results in extensive temperature fluctuations as a result of intense heating and cooling. Therefore, PPCMs have been used in buildings due to their ability to regulate and stabilize indoor temperatures at higher or lower outdoor temperatures [90].
Generally, PPCMs in buildings are used as thermal energy storage at daytime peak temperature, and they released the stored energy at night when temperatures are low. The result of this application is to set the comfort condition for a circadian period. This application minimizes the amount of energy consumed for cooling during the day and warming up at night.
In contrast, in order to stabilize the ambient conditions at low temperatures, some special PCMs are also used in air conditioner systems. In this case, cool air is stored during the night and released into the warm hours of the day.
Y. Cui et al. [91] in a review article categorized PPCM application methods based on their location of use such as PCMs in walls, floor heating systems, ceiling boards, air-based solar heating systems, free cooling systems (with ventilation systems), and PCM shutter (in windows). Both types of encapsulation and shape-stable PPCMs could be used in all of the above classification of building applications. Sometimes these materials can be added directly to concrete, gypsum, etc. [90, 92, 93, 94, 95].
In order to increase the performance of PPCMs in this application field, great deals of studies have also been done on improving their thermal conductivity. On the other hand, extensive research into safety issues has been done to reduce the flammability of PPCMs by adding flame retardants to these materials.
Overall, these studies cover the importance of using PPCMs in heating and cooling as well as indicate the general characteristics, advantages, and disadvantages of these materials used for thermal storage in buildings.
It is clear that at this time, where renewable energy is particularly important, the use of PPCMs is on the rise. As it has been mentioned, PPCMs have many application fields due to their advantages. For example, they can be used in the construction, pharmaceutical and medical industries, textiles, automobiles, solar power systems, transportation, thermal batteries, heat exchangers, and so on.
This chapter of the book has attempted to focus more on how to use paraffins. For this reason, two methods, namely, encapsulation and shape-constant, have been widely discussed. In addition, improving their weak properties such as thermal conductivity and flammability has also been studied. Depending on the benefits of paraffins, new applications are suggested every day. Extensive studies are underway on other new applications in recent years.
As an Open Access publisher, IntechOpen is dedicated to maintaining the highest ethical standards and principles in publishing. In addition, IntechOpen promotes the highest standards of integrity and ethical behavior in scientific research and peer-review. To maintain these principles IntechOpen has developed basic guidelines to facilitate the avoidance of Conflicts of Interest.
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\\n\\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\\n\\nA Conflict of Interest can be identified at different phases of the publishing process.
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\\n\\nAvoidance Measures for Academic Editors of Conflicts of Interest:
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\\n\\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\\n\\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
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\\n\\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\\n\\nPolicy last updated: 2016-06-09
\\n"}]'},components:[{type:"htmlEditorComponent",content:"In each instance of a possible Conflict of Interest, IntechOpen aims to disclose the situation in as transparent a way as possible in order to allow readers to judge whether a particular potential Conflict of Interest has influenced the Work of any individual Author, Editor, or Reviewer. IntechOpen takes all possible Conflicts of Interest into account during the review process and ensures maximum transparency in implementing its policies.
\n\nA Conflict of Interest is a situation in which a person's professional judgment may be influenced by a range of factors, including financial gain, material interest, or some other personal or professional interest. For IntechOpen as a publisher, it is essential that all possible Conflicts of Interest are avoided. Each contributor, whether an Author, Editor, or Reviewer, who suspects they may have a Conflict of Interest, is obliged to declare that concern in order to make the publisher and the readership aware of any potential influence on the work being undertaken.
\n\nA Conflict of Interest can be identified at different phases of the publishing process.
\n\nIntechOpen requires:
\n\nCONFLICT OF INTEREST - AUTHOR
\n\nAll Authors are obliged to declare every existing or potential Conflict of Interest, including financial or personal factors, as well as any relationship which could influence their scientific work. Authors must declare Conflicts of Interest at the time of manuscript submission, although they may exceptionally do so at any point during manuscript review. For jointly prepared manuscripts, the corresponding Author is obliged to declare potential Conflicts of Interest of any other Authors who have contributed to the manuscript.
\n\nCONFLICT OF INTEREST – ACADEMIC EDITOR
\n\nEditors can also have Conflicts of Interest. Editors are expected to maintain the highest standards of conduct, which are outlined in our Best Practice Guidelines (templates for Best Practice Guidelines). Among other obligations, it is essential that Editors make transparent declarations of any possible Conflicts of Interest that they might have.
\n\nAvoidance Measures for Academic Editors of Conflicts of Interest:
\n\nFor manuscripts submitted by the Academic Editor (or a scientific advisor), an appropriate person will be appointed to handle and evaluate the manuscript. The appointed handling Editor's identity will not be disclosed to the Author in order to maintain impartiality and anonymity of the review.
\n\nIf a manuscript is submitted by an Author who is a member of an Academic Editor's family or is personally or professionally related to the Academic Editor in any way, either as a friend, colleague, student or mentor, the work will be handled by a different Academic Editor who is not in any way connected to the Author.
\n\nCONFLICT OF INTEREST - REVIEWER
\n\nAll Reviewers are required to declare possible Conflicts of Interest at the beginning of the evaluation process. If a Reviewer feels he or she might have any material, financial or any other conflict of interest with regards to the manuscript being reviewed, he or she is required to declare such concern and, if necessary, request exclusion from any further involvement in the evaluation process. A Reviewer's potential Conflicts of Interest are declared in the review report and presented to the Academic Editor, who then assesses whether or not the declared potential or actual Conflicts of Interest had, or could be perceived to have had, any significant impact on the review itself.
\n\nEXAMPLES OF CONFLICTS OF INTEREST:
\n\nFINANCIAL AND MATERIAL
\n\nNON-FINANCIAL
\n\nAuthors are required to declare all potentially relevant non-financial, financial and material Conflicts of Interest that may have had an influence on their scientific work.
\n\nAcademic Editors and Reviewers are required to declare any non-financial, financial and material Conflicts of Interest that could influence their fair and balanced evaluation of manuscripts. If such conflict exists with regards to a submitted manuscript, Academic Editors and Reviewers should exclude themselves from handling it.
\n\nAll Authors, Academic Editors, and Reviewers are required to declare all possible financial and material Conflicts of Interest in the last five years, although it is advisable to declare less recent Conflicts of Interest as well.
\n\nEXAMPLES:
\n\nAuthors should declare if they were or they still are Academic Editors of the publications in which they wish to publish their work.
\n\nAuthors should declare if they are board members of an organization that could benefit financially or materially from the publication of their work.
\n\nAcademic Editors should declare if they were coauthors or they have worked on the research project with the Author who has submitted a manuscript.
\n\nAcademic Editors should declare if the Author of a submitted manuscript is affiliated with the same department, faculty, institute, or company as they are.
\n\nPolicy last updated: 2016-06-09
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He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). 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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). 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