\r\n\tNeck pain is poorly understood and managed. Whiplash remains a controversial subject. The role of surgery in neck pain versus conservative treatment. \r\n\tThis book aims to provide a clear understanding of how to differentiate between the causes of shoulder and neck pain, which investigations are appropriate and how to treat once a diagnosis has been made. Controversies in current understanding will be discussed and some light shone upon them.
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1. Introduction
The non-renewable fossil resources currently exploited by the oil and gas industries are the objects of growing concern owing to their finite supply and contribution to global warming. Lignocellulosic biomass is a sustainable alternative to fossil resources, and has the added advantage of not competing with human and animal nutrition. Indeed, lignocellulosic biomass, in particular its main polymer component cellulose, is a potential carbon source for the production of fuels and commodity chemicals in microbes.
Hydrolysis of cellulose polymer molecules to liberate the readily fermentable glucose they contain is a necessary step in their use as feedstock by fermenting organisms. The hydrolysis of cellulose is typically carried out by glycoside hydrolase enzymes termed cellulases, and produced by specialist microorganisms. Organisms that naturally feed on and hydrolyse cellulose are mainly found among filamentous fungi, such as the highly exploited Trichoderma reesei, and obligate anaerobic bacteria such as those of the Clostridium genera. The complete breakdown of cellulose to glucose requires the cooperation of three different types of cellulases. Endoglucanases (EGLs) cleave amorphous cellulose randomly at endo sites to release cellodextrins of various lengths. Cellobiohydrolases (CBHs), on the other hand, are required for the hydrolysis of crystalline cellulose, and release cellobiose by acting at the reducing and non-reducing ends of cellulose strands [1, 2]. Finally, β-glucosidases (BGLs) produce glucose from the hydrolysis of the cellobiose and cello-oligomers produced by EGLs and CBHs. The three types of enzymes are believed to act synergistically. EGLs cleave at random inside strands, creating termini for CBHs, which in turn contribute to loosening of cellulose crystallinity, making further material available to EGLs [2]. Some cellulases, as well as other proteins involved in cellulose degradation, carry a cellulose-binding domain (CBD) that acts to tether them to their polymeric substrate, and allows them to processively degrade cellulose by crawling along its strands [3]. Certain organisms assemble their cellulases on their cell surface as multi-enzyme complexes termed cellulosomes, notably to enhance synergy between enzymes and promote substrate channelling [4].
The bionconversion of cellulose to biofuels or commodity chemicals must proceed through several steps. Following pre-treatment of the biomass, cellulose is hydrolyzed as described in the above paragraph. The glucose liberated by cellulose hydrolysis can then be fed to microbes that produce compounds of interest, for example the yeast Saccharomyces cerevisiae, which ferments it to ethanol. Doing these two steps one after the other is known as sequential hydrolysis and fermentation (SHF). It requires the addition of costly cellulase cocktails separately produced by fungi, and accumulation of glucose during the hydrolysis step leads to end product inhibition. The capital cost of having multiple separate steps, and the time required for sequential conversion processes further reduce the profitability of sequential hydrolysis and fermentation [5]. Simultaneous saccharification and fermentation (SSF) reduces the number of steps and alleviates the end-product inhibition issue, however it still requires the addition of exogenous cellulases [6]. To further reduce costs, a strategy known as consolidated bioprocessing (CBP) has been proposed, which entails the in situ production of cellulases by the fermenting organism. This strategy consolidates enzyme production, hydrolysis and fermentation into a single step. However, CBP requires an organism efficient at both degrading cellulose and fermenting glucose to a single product at high titers. Such an organism does not exist in nature [7]. To overcome this obstacle, two solutions can be envisioned. Efficient cellulose degraders may be engineered to produce chemicals of interest, or alternatively, organisms that natively produce such compounds can be endowed with recombinant cellulase genes.
Thus, the recombinant expression of cellulases, or cellulase systems, enables CBP. It may also be used to reduce exogenous enzyme loads required by SSF, and may have benefits for the production of the cellulase cocktails used in both SHF and SSF. The recombinant and heterologous expression of cellulases in microorganisms may also benefit other industries. The textile industry, for example, uses cellulases to create stonewashing effects on cellulose-derived clothing fibres. Use of cellulase-expressing lactic acid bacteria, on the other hand, is of interest for the ensilage of hay fed to livestock. For these reasons, considerable research has been done to engineer organisms that express recombinant cellulases and cellulase systems. The aim of this chapter is to review the progress made in the engineering of such organisms. We first review the production of cellulases expressed as freely secreted or cell surface-anchored enzymes, and divide our discussion based on the types of organisms engineered (yeast, bacteria, then fungi). We then put special emphasis on the production of artificial recombinant cellulosomes and cellulosome-inspired architectures, outlining the different manners in which they can be assembled, and which microorganisms were used to do so.
2. Cell surface-anchored and secreted recombinant cellulase systems
The scientific literature is ripe with examples of secreted or surface-anchored recombinant cellulases and cellulase systems expressed in yeast, bacterial and fungal hosts. Most research has focused on a handful of organisms, namely Saccharomyces cerevisiae, the enteric bacteria Escherichia coli and Klebsiella oxytoca, the gram-negative bacterium Zymomonas mobilis, and the cellulolytic fungus Trichoderma reesei. Other species have garnered less attention, yet represent an interest to the field and should not be dismissed.
This section focuses on work aimed at producing organisms that can efficiently degrade cellulose via the expression of recombinant cellulases. Because the recombinant expression of cellulases was extensively reviewed in a number of publications in the last decade [8-10], the text is centered on the most significant outcomes, and provides an overview of the most recent work.
2.1. Expression of cellulases in yeast
Attempts at expressing recombinant cellulases in yeast abound owing to the traditional role of the brewer\'s yeast Saccharomyces cerevisiae in ethanol production. The use of other yeast species for recombinant expression of cellulases is also discussed in this section, namely species that display interesting metabolic capabilities or stress tolerance characteristics.
2.1.1. Recombinant cellulase expression in Saccharomyces cerevisiae
A significant proportion of recombinant cellulase expression studies were performed in yeast, and almost all of that work was done in Saccharomyces cerevisiae. The millennia-old utilization of this organism for ethanol production, its relatively well-studied physiology, and the diversity of readily available tools for its genetic manipulation mean that it is an important candidate for the engineering of a cellulose-degrading ethanologen.
Since the 1990s, numerous cellulases from various bacterial and fungal sources were cloned and expressed in S. cerevisiae, and those have been reviewed elsewhere [8, 9]. Over the last thirteen years, a few studies representing significant progress towards the production of a cellulose-fermenting yeast strain were published. Cho and coworkers [11, 12] reported an early example of a recombinant yeast strain that could functionally express several cellulases. Using δ-integration, they inserted multiple copies of two cellulase genes - encoding a bifunctional endo/exo-glucanase and a BGL- into the chromosomes of S. cerevisiae. The recombinant organism displayed enhanced growth on cellooligosaccharides when compared to wildtype, and required reduced loads of exogenous cellulases when applied in SSF [12]. However, levels of cellulase expression were deemed low, and did not enable growth and ethanol production using cellulose as the sole carbon source. A later study similarly expressed the three types of cellulases required for cellulose degradation in S. cerevisiae [13]. The EGL and CBH, from Trichoderma reesei, and the BGL, from Aspergillus aculeatus, were co-displayed as α-agglutinin fusions on the surface of yeast cells, enabling the liberation of glucose from phosphoric acid swollen cellulose (PASC), and fermentation to ethanol when the cells were pre-grown in rich media. Den Haan and coworkers [14] reported similar accomplishments, co-expressing an EGL from T. reesei and a BGL from the yeast Saccharomycopsis fibuligera in S. cerevisiae. This study was allegedly the first report of direct conversion of cellulose to ethanol by cellulase-expressing yeast, as it was reported that the engineered strain could grow and produce modest yields of ethanol (1.0 g/L in 192 hours) from PASC in media also containing yeast extract and peptone (YP-PASC). A study published almost simultaneously by the same authors reported the low level expression of CBHs in yeast [15], but expression of these enzymes in the PASC-fermenting BGL/EGL background was not reported.
Following these milestone studies, other groups reported on the expression of cellulases in S. cerevisiae and their use for fermentation of cellulose to ethanol. Jeon and coworkers reported the expression of EglE from Clostridium thermocellum and BGL1 of S. fibuligera in the budding yeast. The resulting yeast strain could produce ethanol from carboxymethyl cellulose (8.56 g/L, 16 hours), β-D-glucan (9.67 g/L, 16 hours) and PASC (7.16 g/L, 36 hours) after pre-culturing in synthetic galactose medium and extensive washing in minimal media [16]. This was a progress compared to previous studies, in that it did not require yeast extract or peptone to produce ethanol from cellulosic substrates. Another study [17] compared the performance of two recombinant yeast strains in directly converting cellulose to ethanol in YP-PASC medium. A BGL from A. aculeatus was anchored to the cell surface, while an EGL and a CBH were either anchored or secreted. Higher ethanol yields were obtained when all three enzymes were surface-anchored. These results suggested that this configuration enhances the ability of yeast to degrade cellulose and use the resulting sugars in a manner reminiscent of cellulosome-enzyme-microbe complexes (discussed in Section 3).
Direct conversion of cellulose to ethanol poses the problem of finding the optimal ratios of the different types of cellulase. A novel strategy, termed cocktail δ-integration was recently proposed to address this issue [18]. This strategy involves the simultaneous transformation and integration in the yeast chromosomes of BGLs, EGLs and CBHs on a single DNA fragment with a single selection marker. Fragments are designed to carry varying numbers of each cellulase gene. Integrants are then compared in their ability to degrade cellulose, and those with the best ratios can be identified. The procedure can be repeated several times using different selection markers. After three rounds of cocktail δ-integration, Yamada and coworkers [18] were able to generate a strain with twice the activity on PASC, but half the number of cellulase genes than a similar strain generated using a conventional method. These results strongly argue for a successful optimization of cellulase ratio. The activity of the ratio-optimized strain was further improved by making it diploid [19]. The optimized diploid showed an ability to produce ethanol directly from PASC (7.6 g/L in 72 hours) or pretreated rice straw (7.5 g/L) in yeast peptone (YP) medium without addition of exogenous enzymes. This was the first report of direct conversion to ethanol of agricultural waste residue without exogenous enzyme addition by recombinant cellulase-expressing yeast [19]. Other strategies used to incorporate enzymes at specific ratios into artificial cellulosomes using yeast consortia are discussed later in this chapter (Section 3.4.1).
Two independent studies gave examples of improved SSF using cellulase-expressing yeast. One study [20] reported the transformation of an industrial strain with a BGL-carrying plasmid, enabling the use of cellobiose as the sole carbon source and its conversion to ethanol, producing 3.3 g/L in 48 hours. When supplementing with exogenous cellulases, the strain was shown to produce 20 g/L of ethanol from pre-treated corncobs, a yield similar to outcomes obtained with the parent strain supplemented with additional BGL. Another SSF study [21] reported the production of 7.94 g/L of ethanol in 24 hours from barley β-D-glucan using yeast co-displaying a BGL and an EGL from Aspergillus oryzae.
In recent years, a few thermotolerant enzymes have been expressed in S. cerevisiae. For example, BGL4 from Humicola grisea was recently cloned in the budding yeast [22]. Interestingly, the recombinant enzyme displayed resistance to glucose inhibition in addition to thermotolerance. Others have reported on the expression of thermotolerant cellulases in yeast using a mutagenesis and recombination strategies rather than a discovery approach to further improve stability and activity of the recombinant enzymes [23-25].
Inadequate secretion of cellulases by recombinant yeast is an obstacle to their successful application in an industrial context. To address this issue, a library of approximately 4800 non-essential deletion mutants was systematically transformed with a plasmid carrying an endoglucanase gene from the bacterium C. thermocellum [26]. Mutants were compared in their ability to degrade carboxymethyl cellulose, and 55 of them showed increased activity. The mutants covered a large spectrum of cellular functions, including transcription, translation, phospholipid synthesis, endosome/vacuole function, ER/Golgi function, nitrogen starvation response, and the cytoskeleton. The effect of a subset of these mutations was tested on the level of activity of another cellulase, a BGL from A. aculeatus. Interestingly, five out of the nine mutations tested increased BGL activity in addition to EGL activity, suggesting that certain mutations may increase the secretion level of several cellulases, and potentially all enzymes within a cellulase system [26].
2.1.2. Recombinant cellulase expression in other yeast species
While most studies expressing recombinant cellulase systems in yeast have used Saccharomyces cerevisiae, other species, superior to brewer\'s yeast in some respects, have also been used.
The yeast Scheffersomyces stipitis (formerly Pichia stipitis) is one of the organisms considered for its potential in the bioconversion of lignocellulosic biomass, owing to its native cellulase activity, but foremost to its pentose-fermenting capabilities. Indeed, hemicellulose, the second most abundant sugar polymer of plant cell walls after cellulose, is composed largely of xylose, which S. cerevisiae cannot ferment. S. stipitis, on the other hand, produces the largest yields of ethanol from xylose that have been observed to date [27]. S. stipitis naturally consumes lignocellulosic biomass, therefore cellulase activity, notably β-glucosidase activity, has been detected in this organism [28], while its genome was found to encode several putative cellulolytic enzymes [29]. Yet, during the development of molecular genetics tools for S. stipitis, recombinant cellulases were used as reporters of protein expression [30].
Saccharomyces cerevisiae is generally not viable in conditions of temperature optimal for cellulase activity. Indeed, cellulases from the common cellulolytic microbes C. thermocellum and T. reesei are found to lose most of their activity at temperatures below 40°C [31], while S. cerevisiae grows poorly above 38°C [32] and could not so far be engineered to remain productive at temperatures that exceed 42°C [33]. In addition, acids are commonly used in the pretreatment of lignocellulosic biomass, while both high temperatures and acidic conditions can be used in preventing contamination during fermentation. For these reasons, expression of recombinant cellulase systems has been attempted in a few stress tolerant species of yeast. For example, the thermotolerant Kluyveromyces marxianus was used in a number of SSF studies in which cellulases were added exogenously [34-37]. The strain was subsequently engineered to express three thermostable cellulases, endowing it with the ability to grow at 45°C on both cellobiose and carboxymethyl cellulose and to ferment cellobiose to ethanol [38]. The multi-stress tolerant Issatchenka orientalis was also successfully engineered for recombinant cellulase expression. This organism is tolerant to acid, salt and elevated temperature, in addition to being ethanol tolerant, making it a suitable candidate for cellulose bioconversion [39]. Kitagawa and coworkers [40] provided the first report of heterologous gene expression in I. orientalis, isolating and cloning the necessary auxotrophy markers and building a recombinant cassette for the production of A. aculeatus BGL. The engineered strain showed BGL activity and was able to grow and produce ethanol on cellobiose in conditions of elevated temperature, acidity and salinity. SSF trials using this strain achieved measureable ethanol outputs, albeit at lower levels than what was obtained with the parental strain supplemented with exogenous BGL. Still, to achieve similar yields, reduced BGL supplementation was required for the recombinant strain.
2.2. Expression of cellulases in bacteria
This section reviews recent research aimed at expressing recombinant cellulases in bacteria. Although the workhouse and longtime protein overproducing Escherichia coli has received significant interest, several other species with specialized functions have also been exploited. These functions include: the ability to assimilate cellulose-derived oligosaccharides, native production of biofuel molecules or organic acids, and thermophilicity.
2.2.1. Recombinant cellulase expression in enteric bacteria
The enteric bacterium E. coli has a long history of being used for the expression of recombinant proteins, and numerous tools for the genetic engineering of this organism are readily available. Furthermore, E. coli has among the simplest and cheapest growth requirements. It is thus an attractive canvas for the engineering of a cellulose-utilizing industrial strain. Therefore, it comes to no surprise that studies have reported the heterologous expression of cellulase systems in this organism. Significant advances have also been reported in Klebsiella oxytoca, a bacterium related but superior to E. coli in its native ability to assimilate and use cello- and xylo-oligosaccharides.
Wildtype E. coli and K. oxytoca are not prolific ethanologens and neither have cellulolytic activity. The classical strategy to turn these organisms into ethanol producers is to endow them with an alcohol dehydrogenase and a pyruvate decarboxylase genes from the ethanologenic bacterium Zymomonas mobilis (Section 2.2.2) [41]. It is normally with this background that enteric bacteria have been used for recombinant cellulase expression. Several papers over the course of the last twenty years have reported the engineering of E. coli and K. oxytoca in this manner [42-47]. The most advanced examples report the expression of the endoglucanase genes celY and celZ from the phytopathogenic bacterium Erwinia chrysanthemi in an ethanologenic K. oxytoca background [46, 47]. This recombinant cellulase system, in conjunction with the native BGL activity of K. oxytoca enabled the direct conversion of crystalline cellulose to ethanol with addition of exogenous cellulases [46], while amorphous cellulose could be readily converted to ethanol without exogenous cellulase supplementation [47]. However, as is the case for reports of direct cellulose-to-ethanol conversion by yeast, these successes depended on the presence of yeast extract and peptone in the fermentation medium.
More recently, a proof-of-concept study by Bokinsky and coworkers [48] reported the expression of complete sets of cellulases and hemicellulases in E. coli for the conversion of lignocellulosic biomass to second-generation biofuels. In this study, a library of EGLs was tested for expression in E. coli, while collections of BGL and xylobiosidases were evaluated for their ability to enable growth of E. coli on cellobiose and xylobiose, respectively. The best EGL and BGL genes were introduced into E. coli to generate a cellulose-degrading strain. The best xylobiosidase was similarly combined with a previously identified xylanase to generate a hemicellulose-degrading strain. Growth on ionic liquid-pretreated lignocellulosic feedstock (switchgrass, eucalyptus and yard waste) was demonstrated. Combining both strains allowed enhanced growth on all substrates. The strains were further engineered to express one of three operons for the production of advanced biofuel molecules (fatty acyl ethyl esters, butanol or pinene) from ionic liquid-pretreated switchgrass, achieving modest yields. This study is the first report of a complete cellulose-to-biofuel conversion in bacteria using natural feedstock. Moreover, no exogenous cellulases were added, and all hydrolysis and fermentation experiments in this study were performed in minimal media with cellulose or hemicellulose as the sole carbon source.
2.2.2. Recombinant cellulase expression in Zymomonas mobilis
Zymomonas mobilis is an ethanologenic gram-negative bacterium. Unlike S. cerevisiae, it converts glucose to ethanol via the Entner-Doudoroff pathway, enabling ethanol yields that could more closely match theoretical yield values than the classical glycolytic pathway. It is considered superior to brewer\'s yeast in other respects. Indeed, it has higher tolerance to ethanol, enabling superior yields, which it produces with high productivities [7, 49-55]. Therefore, several reports of recombinant cellulase expression in Z. mobilis have been published [55-59]. Among early reports of recombinant cellulase expression in Z. mobilis [56-58], only one succeeded in exporting an EGL to the extracellular milieu using the protein\'s native signal [56]. In that study, approximately 10% of the EGL protein was found to be extracellular, while most of the cell-associated activity was found in the periplasm [56]. Recent studies fused recombinant cellulases to native Z. mobilis export signals in an attempt to direct a larger proportion of the enzymes to the extracellular milieu. In one study, a BGL from Ruminococcus albus was fused to the glucose–fructose oxidoreductase and gluconolactonase export signals of Z. mobilis, resulting in the secretion of only 4.7% and 11.2% of the protein, respectively. The resulting strain was able to use cellobiose and ferment it to ethanol [55]. A more recent study used two different secretion signals native to Z. mobilis, and suggested to use distinct pathways. These endogenous signals were fused to the catalytic domain of two Acidothermus cellulolyticus EGLs, enabling the export of 40%-50% of the recombinant cellulases to either the periplasm or extracellular milieu [59]. This latter study did not report on the ability of the strains to grow on or convert cellulosic substrates. Interestingly, it provided a confirmation to an earlier study that suggested the presence of endogenous cellulase activity in Z. mobilis [60].
2.2.3. Recombinant cellulase expression in other bacterial hosts
Other bacterial species with useful industrial properties have been used for the expression of recombinant cellulases. Species such as Clostridium acetobutylicum and Clostridium beijerinckii can be used in the industrial scale production of solvents and biofuels in the acetone-butanol-ethanol (ABE) process [61]. Enthusiasm for biofuels and synthetic biology in recent years has renewed interest for the high yields of solvents, in particular butanol, achieved by these organisms. The classical source of carbon for the ABE process was potato starch, however recent research has been aimed at enabling the use of cellulose, a more sustainable and industrially suitable carbon source, by solventogenic Clostridium. The genome of C. acetobutylicum encodes genes for putative cellulosome components, which will be discussed later in this chapter (Section 3.3.2). However, growth of this microbe, while successful on hemicellulose [62, 63] has so far not been observed with cellulose as the sole carbon source [64], despite observations that various substrates induce the expression of cellulases in C. acetobutylicum [65, 66]. Therefore, solventogenic Clostridium were engineered to express recombinant cellulases. Most efforts were aimed at reconstituting functional Clostridium cellulolyticum cellulosomes in C. acetobutylicum, but expression of isolated cellulases was also attempted. In an early study, an EGL from the cellulolytic bacteria Clostridium cellulovorans was expressed in C. acetobutylicum [67]. While the resulting strain could degrade carboxymethyl cellulose in Congo Red plate assays, it failed to grow on cellulose as the sole carbon source. Mingardon and coworkers expressed six C. cellulolyticum cellulases in C. acetobutylicum and found that three enzymes, those with lower molecular weights, were successfully secreted [68]. The larger enzymes failed to generate viable clones, or led to accumulation of cellulase protein in the cytoplasm. In a subsequent study, the same group reported the successful secretion of large cellulases by fusing them to sequences of scaffoldins and cellulose binding modules of C. cellulolyticum [69]. The related species C. beijerinckii was also used for the heterologous expression of recombinant cellulases. Expression of an EGL from the cellulolytic fungus Neocallimastix patriciarum in C. beijerinckii yielded results that resembled those observed with C. acetobutylicum. Indeed, the recombinant C. beijerinckii strain displayed cellulolytic activity in Congo Red plate assays, but failed to grow on cellulose. Interestingly, the fungal EGL improved growth and solvent yields of the microbe on lichenan, a polymer of glucose similar to cellulose [70].
Lactic acid bacteria (LAB) have also served as hosts for recombinant cellulase expression. The interest of LAB lies in their potential as silage inocula, probiotics, and industrial lactic acid producers. Several LAB species, including Lactobacillus plantarum and Lactococcus lactis have been engineered for the improved lactic fermentation of forage by expressing cellulose-degrading enzymes. Early studies reported the successful expression and secretion of functional EGLs from plasmids [71] or from the chromosome [72] in L. plantarum. Chromosome integration of a Bacillus sp. EGL in L. plantarum was later shown to elicit increased acidification of forage in micro-ensiling experiments [73]. Similarly, L. lactis was transformed with a cellulase gene from the rumen fungus Neocallimastix sp. [74]. The recombinant L. lactis strain enhanced the digestibility of forage when used in ensiling experiments. Lactobacilli species L. gasseri and L. johnsonii, natural inhabitants of the mammalian gastrointestinal tract, were also engineered to express a C. thermocellum endoglucanase [75]. The aim of this study was to generate probiotics that would facilitate digestion of plant cell walls by monogastric animals, thus alleviating the need for the onerous supplementation of animal feed with exogenous cellulases. The resulting strains displayed cellulase activity on carboxymethyl cellulose, and had characteristics desirable for probiotics. A lactate dehydrogenase-deficient strain of L. plantarum was later engineered to express a C. thermocellum EGL, allowing the successful hydrolysis and conversion of barley β-D-glucan to lactic acid in anaerobic conditions, achieving best yields with addition of exogenous BGL [76].
We have already mentioned the relevance and interest of thermotolerant or thermophilic enzymes for the bioconversion of cellulose. While tools for the genetic engineering of thermophilic bacteria are still in their infancy [77], one example of cellulase expression is found in the thermophile Thermoanaerobacterium saccharolyticum [78]. In this study, development of recombinant protein expression systems used cellulases and other glycoside hydrolases from C. thermocellum as test proteins, and cellulase activity was detected.
2.3. Expression of cellulases in fungi
Several species of fungi are superior protein secretors, and as such show high potential for the industrial-scale production of enzymes. Not surprisingly, the cellulase cocktails used in industry for the bioconversion of cellulose or for the treatment of textile fibers are typically produced by cellulolytic fungi [79]. The organism most commonly used for this purpose is the filamentous fungus Trichoderma reesei, because of the high titers of cellulase enzymes that it secretes [80]. Recombinant approaches have been applied to enhance the production of native cellulases or to express heterologous cellulolytic enzymes in T. reesei and other fungi.
To increase yields of EGL produced by T. reesei, Miettinen-Oinonen and Suominen reported a strategy whereby the native cbh2 locus was disrupted to redirect the secretory capabilities of the fungus towards other proteins [81]. This CBH-deficient background was transformed with constructs of T. reesei EGL genes placed under the control of the strong cbh2 promoter. These modifications, coupled to an increase in EGL copy number, were successful in augmenting the levels of secreted EGL, and in increasing the performance of the T. reesei-secreted enzyme in stonewashing treatment of denim fabric. A follow-up study by the same group tested the effect of promoter swapping, deletion of native enzymes, and copy number increase on the level of CBH secretion, yielding comparable results [82]. Another approach aimed at increasing the activity of the T. reesei-secreted cellulase cocktail was to fuse an A. cellulolyticus EGL domain to native CBH expressed in T. reesei. The resulting bi-functional enzyme increased the saccharification yields of T. reesei [83].
Several studies have reported the heterologous expression of thermophilic fungal cellulases in mesophilic fungi, notably T. reesei, Aspergillus oryzae and Humicola insolens (reviewed in [84]). For example, protein variants of the Cel12A enzyme of T. reesei rationally designed for increased thermal stability and activity were expressed in the efficient protein secretor Aspergillus niger [85]. In another study, the cellobiohydrolase Cel7A from T. reesei was expressed in A. niger, and mass spectrometry was used to compare N-glycosylation between the recombinant and the native protein. The cellobiohydrolase contained six times more N-linked glycans when expressed in A. niger, and its activity was reduced, underlining the critical effect of post-translation modifications on recombinant cellulases [86]. Recently, a library of EGLs from various fungi were cloned and expressed in A. niger [87]. Both activity and level of expression were compared to that of TrCel5A, one of the major endoglucanases from T. reesei. This screen identified three EGLs, from species Aureobasidium pullulans, Gloeophyllum trabeum and Sporotrichum thermophile with expression levels and hydrolysis performances superior to those of the Trichoderma enzyme [87].
3. Recombinant cellulosomes
The degradation of recalcitrant cellulosic substrates into fermentable carbohydrates requires multiple catalytic activities [4]. Many cellulolytic fungi are capable of degrading crystalline cellulose by secreting cocktails of free hydrolytic enzymes [88]. Alternatively, the hydrolysis of cellulosic substrates can be carried out by macromolecular enzyme complexes [4]. The incorporation of enzymes in a larger multi-enzyme complex yields several benefits associated with substrate channeling as well as synergy among neighboring enzymes [89]. Substrate channeling refers to the flow of intermediate metabolites from one reaction to another, where individual catalytic activities are co-localized in a central protein scaffold. In the case of cellulose hydrolysis, longer chain polysaccharides produced by non-processive cellulases become the substrate for processive cellulases, which can produce short chain cellodextrins and cellobiose as primary products. Enzyme synergy results when the sum of individual enzyme activities is augmented by their incorporation in multi-enzyme complexes. From a biotechnological perspective, optimizing the spatial organization of enzymes through co-localization can greatly enhance the channeling of hydrolysis intermediates to enzymes that will use them as substrates. A number of cellulolytic bacteria have evolved to assemble multi-enzyme complexes such as cellulosomes. Cellulosomes have become inspiration for the engineering of recombinant complexes with defined enzyme compositions. For instance, the thermophilic bacterium C. thermocellum, which is documented to have one of the most efficient system for cellulose hydrolysis [89], produces one of the most thoroughly studied and well-characterized cellulosomes. The engineering of multiple cellulases into macromolecular cellulolytic complexes is a strategy that has been adopted by a number of research groups in the development of microorganisms that can degrade cellulose and produce commodity chemicals and biofuels.
3.1. Nature’s building blocks for engineering recombinant cellulosomes
Cellulosomes are cellulose-degrading protein complexes comprised of a multitude of hydrolytic enzymes with varying catalytic activities that associate with a central scaffold protein [90]. The variability in architecture of cellulosomes from different organisms has been a significant source of inspiration for the engineering of protein scaffolds and multi-enzyme complexes [91-94]. The assembly of the cellulosome complex is mediated via non-covalent interactions between non-catalytic dockerin and cohesin domains. These domains serve as the building blocks that hold the complex together and dictate its architecture. Two characteristics of a dockerin and cohesin pair determine the specificity of the interaction: the species from which they are derived, as well as the type of interaction. Type 1 and type 2 cohesins from a single organism do not interact with dockerins of the opposite type (e.g. type 1 cohesins do not interact with type 2 dockerins, and vice-versa). In the case of C. thermocellum, type 1 dockerins and cohesins mediate the interaction between enzymes and scaffold proteins, while type 2 dockerins and cohesins mediate binding of scaffolds and cell surface anchor proteins. Cellulosomal enzymes carry type 1 dockerin domains which bind any of the nine type 1 cohesin domains found on the central scaffold protein CipA [95]. Cellulosomal scaffolds such as CipA typically contain a CBD that brings the complex in close proximity to the cellulose fibers, allowing the different cellulases to act in synergy on the crystalline substrate. CipA protein also carries a type 2 dockerin domain, which interacts with type 2 cohesins located on cell wall anchor proteins OlpB and SdbA [96, 97]. These anchor proteins ensure the attachment of the complex on the cell surface. In addition, cohesin and dockerin domains derived from different organisms do not bind with one another. Therefore, cohesins and dockerins from different species as well as those of different types have become the building blocks used by researchers to engineer custom-designed recombinant cellulosomes or cellulosome-inspired complexes with precise compositions. The strategies adopted by most researchers in this effort can be divided into three categories discussed in subsequent sections. These include (i) the production of recombinant enzymes and scaffolds in host strains followed by their purification and assembly in vitro (Figure 1A), (ii) the production of all components in a single strain resulting in the in vivo assembly of resulting complexes in the culture supernatant (Figure 1B), and (iii) the surface-tethering of scaffolds towards the in vivo assembly of artificial cellulosomes on the cell surface of the host organism (Figure 1C).
3.2. In vitro assembly of recombinant cellulosomes
The assembly of custom-designed cellulosomes initially involved the production of individual components in an organism of choice, followed by their purification and assembly in vitro. Desirable characteristics for a bacteria designed to overexpress individual components include ease of manipulation of the organism, and low endogenous proteolytic activity. Since multiple strains are used to generate individual components, this strategy is not limited to a single organism being used for the production of each recombinant subunit, since further purification and in vitro assembly of the final complex is required (Fig. 1A).
Figure 1.
Strategies for the assembly of artificial cellulosome complexes. (A) Enzyme-dockerin fusions and scaffold chimeras are produced by different strains of a host organism (e.g. S1, S2, S3, S4), purified, and subsequently assembled in vitro. (B) Enzymes and scaffold subunits are secreted by a single host organism into the culture supernatant where they self-assemble into cellulosomes in vivo. (C) A host organism tethers a scaffold to its surface while secreting recombinant enzyme-dockerin fusions, resulting in the in vivo assembly of the cellulosome complex on the cell surface.
3.2.1. Expression of cellulosome components in E. coli
Early work on the in vitro assembly of cellulosomes focused mostly on demonstrating the effects of having cellulase enzymes bound to a scaffold on activity towards cellulose. In a study by Kataeva and coworkers, the EGL CelD was shown to bind stoichiometrically with fragments of the CipA scaffold protein, and CelD-CipA complexes showed increased activity on cellulose compared with free CelD enzyme. A major observation was that the activity of the complex was dependent on the presence of a cellulose binding domain (CBD), not necessarily the amount of CelD present. The authors hypothesized that the CBD located on the scaffold protein was either indirectly contributing to the hydrolysis process by optimally positioning CelD to act on the crystalline substrate, or that it was playing a more direct role, participating in the partial decomposition of the substrate and ultimately, allowing access to CelD [98]. A subsequent study by Ciruela and colleagues revealed that the binding of another EGL, CelE, with full length CipA, resulted in the assembly of artificial cellulosomes with increased activity on crystalline cellulose compared to free enzymes [99]. Interestingly, although the CBD of CipA was capable of binding both crystalline and amorphous cellulose, the increase in activity observed when CelE was complexed with CipA was only observed on the former, suggesting the pivotal role of the scaffold-enzyme complex in degrading the crystalline substrate. Both studies conducted by Kataeva and Ciruela involved the incorporation of a single enzyme into artificial cellulosomes. Murashima and coworkers used a truncated version of the C. cellulovorans scaffold protein CbpA (Mini-CbpA) and three enzymes, EngE, EngH, and EngS, for the in vitro assembly of artificial cellulosomes containing combinations of two enzymes [100]. Synergy was affected by both the type and stoichiometric ratios of enzyme used. Optimal combinations of enzymes were determined based on increased activity on crystalline cellulose. In this case, however, the effects of relative enzyme positioning within the complex could not be deduced due to the non-specific binding of each enzyme with any of the two cohesins present on the scaffold. The multiple cellulase activities required to degrade crystalline cellulose and the possibility to optimize their positioning within an artificial cellulosome prompted the construction of recombinant protein scaffolds using cohesins with different specificities.
Initial work describing the construction of chimeric scaffolds was carried out by Fierobe and coworkers, where the fusion of cohesins derived from the cellulosomes of C. thermocellum and C. cellulolyticum were used to engineer complexes with dual enzyme activities [101]. The authors engineered a total of four scaffolds that contained two divergent cohesins positioned at various locations relative to the CBD. Two C. cellulolyticum cellulases, CelA and CelF, were engineered to contain either native or C. thermocellum dockerins. All components were over-produced in E. coli, purified and assembled in vitro into three-component cellulosomes. The authors once again demonstrated the necessity of the CBD for increased hydrolysis of the cellulose substrate, and observed that the sequential or simultaneous assembly of each component yielded similar activities. Increased synergy, however, was observed when enzymes were positioned adjacent to each other, suggesting a possible mechanism of substrate channeling between catalytic domains. In a subsequent effort, Fierobe and colleagues successfully generated a library of 75 different chimeric cellulosomes and tested their activities on both crystalline and less recalcitrant substrates [102]. The enzymes incorporated into the bifunctional complexes consisted of a combination of C. cellulolyticum cellulases CelA, CelC, CelE, CelF, or CelG. Synergy due to enzyme assembly on the chimeric scaffolds was only observed when acting on the more recalcitrant substrates such as Avicel and bacterial microcrystalline cellulose, with less or no synergy observed when acting on the less crystalline substrates bacterial cellulose and PASC. To further augment the synergistic and overall activities of bifunctional artificial cellulosomes, Fierobe and coworkers generated trifunctional cellulosomes [91]. In order to control the relative position of the enzymes within the complexe, a third dockerin-cohesin pair derived from Ruminococcus flavefaciens was used in which the interaction is characterized by both high affinity and lack of cross-reactivity with other cohesin-dockerin pairs. Upon incorporation of three cellulases, the complexes demonstrated significantly higher activity than their bifunctional counterparts. The synergy among the complexed enzymes was also demonstrated.
In an effort to generate artificial cellulosome systems with novel geometries and potentially higher overall activities on cellulose, Mingardon and coworkers constructed chimeric scaffolds and cellulases designed to self-assemble in precise spatial arrangements [92]. A hybrid cellulosome consisted of enzymes targeted to a central scaffold, a covalent cellulosome was generated by covalently fusing all components together in a single polypeptide chain, and three other cellulosomes with novel architectures were engineered as well. Still, the hybrid cellulosome, which more closely resembled traditional cellulosome architectures, demonstrated significantly higher activity than all others [92]. Some other notable observations were that the least effective cellulosome contained the most CBDs and that in certain architectures, cohesin-dockerin pairs could dissociate, most probably due to conformational strain.
Cellulosic biomass is mostly composed of lignin and hemicellulose in addition to cellulose. To bestow hemicellulase activity upon engineered cellulosomes, Morais and colleagues intergraded two xylanases as well as a xylose binding domain to a scaffold containing three divergent cohesins from Acetivibrio cellulolyticus, C. thermocellum, and R. flavefaciens [103]. The assembled complexes demonstrated a 1.5 fold increase in activity on hatched wheat straw when compared with the free enzyme mixtures, and the authors attributed this to substrate targeting by the xylose binding domain as well as to the proximity of the enzymes within the complex [103]. This system was further improved in a subsequent study whereby another dockerin-cohesin pair derived from Bacteriodes cellulosolvens was incorporated resulting in a four component artificial cellulosome that could accomodate two EGLs and two xylanases [104]. An overall 2.4-fold increase in activity on hatched wheat straw was observed compared with the free enzyme mixtures.
3.2.2. Expression of cellulosome components in B. subtilis
While E. coli remains an attractive host for the production of enzymes and scaffolds the presence of endogenous proteases can lead to the degradation of desired proteins. Another attractive host towards the production of recombinant cellulosomes is B. subtilis, since it can be easily genetically manipulated, is characterized by fast growth, and is an efficient protein secretor. A strain of B. subtilis deficient in eight major extracellular proteases, B. subtilis WB800, was engineered and used as a host for the production and secretion of C. cellulovorans EngE since this enzyme was shown to be partially degraded in E. coli [105]. Murashima and colleagues were successful in using this protease-deficient strain to produce EngE, and subsequent incubation with scaffold Mini-CbpA, which contains a CBD as well as two cohesins, resulted in assembly of an enzyme-scaffold complex capable of binding cellulose [105].
3.3. In vivo secretion and assembly of recombinant cellulosomes
The overexpression and purification of individual scaffolds and enzymes towards the assembly of artificial cellulosomes poses extra costs and steps towards cellulose hydrolysis. Rather, the development of a CBP-capable organism would require the production, secretion and in vivo assembly of artificial cellulosomes in the extracellular space (Fig. 1B).
3.3.1. Secretion of recombinant cellulosomes by B. subtilis
Initial work began as an extension of Murashima and colleagues’ work employing B. subtilis WB800 as a host for heterologous production of all components. Cho and colleagues constructed an expression cassette encoding both Mini-CbpA and EngE on a single vector which was established in B. subtilis WB800 [106]. The result was the secretion and subsequent assembly of both enzyme and scaffold components into an artificial cellulosome complex which was localized in the supernatant. This study was the first report of the in vivo assembly of artificial cellulosomes by a single organism, although the activity of this strain against cellulosic substrates was not verified. A study by Arai and colleagues used a different approach towards the in vivo assembly of recombinant cellulosomes. In this case, three strains of B. subtilis WB800 were engineered to secrete either EngB, XynB, or MiniCbpA into the culture supernatant [107]. By co-culturing enzyme and scaffold producing strains, complexes formed in the supernatant and were characterized by the appropriate enzymatic activity. This provided a novel method for assembling complexes in vivo based on intercellular complementation.
3.3.2. Secretion of recombinant cellulosomes by C. acetobutylicum
C. acetobutylicum is an organism which has been employed in the production of a number of acids and solvents including acetone, butanol, and ethanol. The potential to engineer this organism to degrade cellulose as a cheap and abundant carbon source has garnered significant attention in the past decade. Interestingly, this bacterium is not cellulolytic, however investigation of its genome sequence reveals a cellulosomal gene cluster encoding a number of hydrolytic enzymes as well as a scaffold protein CipA [64, 108]. Sabathe and colleagues were successful in engineering C. acetobutylicum to secrete and assemble a functional minicellulosome in vivo [109]. Since CipA had been previously demonstrated to not be secreted in this organism, the authors replaced the original signal peptide with that of the C. cellulolyticum scaffold protein CipC. Overexpression and secretion of a truncated version of CipA containing two cohesin domains and a CBD resulted in its binding with endogenous cellulase Cel48A, and formation of a secreted cellulosome in vivo [109]. In analyzing the activity of the recombinant cellulosome on Avicel, bacterial cellulose, PASC and carboxymethyl cellulose, no detectable activity was observed when using the crystalline substrates, as is the case for native C. acetobutylicum. Low levels of activity were observed on carboxymethyl cellulose and PASC, however such levels did not exceed those demonstrated by the native cellulosome. A next logical step was to produce artificial scaffold chimeras in this organism, capable of binding enzymes at very precise locations via divergent cohesin domains derived from different bacterial species. Perret and colleagues first engineered this organism to produce and secrete scaffold miniCipC1 which is a truncated form of C. cellulolyticum scaffold CipC, and subsequently generated chimeric scaffold Scaf3 which contains cohesins from both C. cellulolyticum and C. thermocellum, as well as a CBD [93]. After visualizing the chimeric scaffold using SDS-PAGE, the protein was blotted on a nitrocellulose membrane and was subsequently shown to bind both Cel48 and Cel9 containing a dockerin from C. cellulolyticum, as well as Cel9 with a dockerin from C. thermocellum.
3.4. In vivo surface-anchoring of recombinant cellulosomes
The architecture of the cellulosome establishes proximal and synergistic effects of enzymes within the complex when associated with the substrate [95, 110, 111]. In natural and recombinant systems, these synergistic effects are further augmented by an extra level of synergy resulting from the cellulosome’s association with the surface of cells, yielding cellulose-enzyme-microbe (CEM) ternary complexes [89, 112-118]. CEM ternary complexes benefit from the effects of microbe-enzyme synergy, ultimately limiting the escape of hydrolysis products and enzymes, increasing access to substrate hydrolysis products, minimizing the distance products must diffuse before cellular uptake occurs, concentrating enzymes at the substrate surface, protecting hydrolytic enzymes from proteases and thermal degradation, as well as optimizing the chemical environment at the substrate-microbe interface [89, 112-116]. In several cellulosome-producing bacteria, including C.\n\t\t\t\t\tthermocellum, the cellulosome is anchored to the surface of cells, resulting in one of the most efficient systems for bacterial cellulose hydrolysis [4, 116]. In an effort to mimic such a system, microbial engineers have adopted this strategy as a next logical step towards the improvement of recombinant cellulosome systems with the ultimate goal of increasing the efficiency of the bioconversion process.
3.4.1. Anchoring recombinant cellulosomes on the cell surface of S. cerevisiae
Much interest towards the development of a CBP-capable organism comes from a desire to generate biofuels such as ethanol from cheap and abundant substrates. Therefore, much attention has been directed towards engineering cellulosome systems in ethanologenic organisms such as S. cerevisiae. Lily and colleagues were successful in targeting hybrid scaffold Scaf3p to the cell surface of S. cerevisiae by fusing it with the glycosyl phosphatidylinositol (GPI) signal peptide of the Cwp2 protein for linking to the β-1,6 glucan of the yeast cell wall [119]. The scaffold contained two divergent cohesins from C. thermocellum and C. cellulolyticum as well as a CBD. Microsocopy revealed that the CBD was functional in adhering cells to filter paper, and the successful targeting of a Cel5a-dockerin fusion to the scaffold confirmed functionality of the cohesin modules. The ability to generate scaffold chimeras using non-cohesin modules was established by Ito and colleagues [120]. This research group generated artificial scaffolds by fusing the Z domain of Staphylococcus aureus Protein A with a cohesin from the C. cellulovorans cellulosome and displayed them on the cell surface [120]. The scaffold chimeras were engineered to contain two Z domains as well as two cohesins for precisely targeting different enzymes to the cell surface. The authors fused two enzymes, EGII and BGLI, to either a dockerin domain or Fc domain, which successfully targeted the enzymes to the cohesin and Z domains, respectively [120]. Hydrolysis experiments on β-glucan revealed that co-displaying EGII-FC and BGL-dock resulted in cells capable of degrading this soluble cellulosic substrate, but due to lack of a CBD on the engineered scaffold, this strain would most likely be inefficient at hydrolyzing more recalcitrant cellulosic substrates. A more direct approach to ethanol production was adopted by Tsai and coworkers, where yeast strains were engineered to display a trimeric scaffold containing three divergent cohesins from C. thermocellum, C. cellulolyticum and R. flavefaciens as well as a CBD [121]. Three enzymes, C. thermocellum CelA, and C. cellulolyticum CelE and CelG were overproduced in E. coli and successfully targeted to corresponding cohesin domains on the scaffold by fusion with appropriate dockerin domains, resulting in the surface-display of trifunctional cellulosomes. The anchor system used in this study consisted of displaying the Aga1 protein which interacted with the Aga2 protein fused with the scaffold. Replacing endoglucanase CelG with C. thermocellum β-glucosidase BglA resulted in significant increases in glucose liberation from PASC, and the resulting strain was capable of directly producing ethanol from this substrate. Incubating cells in the presence of PASC resulted in ethanol production that corresponds to 95% of the theoretically attainable ethanol yield. The authors also observed no accumulation of glucose in the medium during the fermentation assays, suggesting that the released glucose was immediately taken up by cells during the SSF process [121].
The production of both enzymes and scaffold in a single yeast strain was achieved by Wen and colleagues [94]. The scaffold contained three cohesins as well as a CBD and was successfully displayed by use of the α-agglutinin adhesion receptor. In vivo secretion of an EGL, CBH, and BGL resulted in the assembly of tetrameric complexes, and the resulting yeast strain was capable of directly converting PASC to ethanol at a yield of 1.8 g/L. Interestingly, the authors also observed that when Bgl1 was positioned within the complex, in close proximity to EGII and CBHII, increased activity was observed, most probably due to removal of the cellobiose at the cell surface which may have been inhibiting EGII and CBHII. In comparison with the work by Tsai and colleagues, this represented the first report of producing and assembling a trifunctional cellulosome on the cell surface by the in vivo production of all components. The relatively low levels of EGII and Bgl1 produced by this strain, however, suggested that burdening the secretion machinery of the organism was a potential bottleneck. To address this issue, the Chen group adopted a different approach towards the in vivo assembly of trifunctional complexes on the cell surface which entailed intercellular complementation by a yeast consortium [122]. In this case, one strain produced a trifunctional scaffold containing three divergent cohesins and a CBD, while each of three other strains produced an exoglucanase, EGL, or BGL which were targeted to specific sites on the artificial scaffold by fusion with corresponding dockerin domains. The authors also reported that an optimal ratio of each strain within the consortium resulted in two-fold increase in ethanol production when compared with a consortium containing equal proportions of each strain.
3.4.2. Anchoring recombinant cellulosomes on the cell surface of L. lactis
While of the attention to the engineering of organisms to display artificial cellulosomes has been directed towards ethanol-producing microbes, the metabolic diversity among microorganisms suggests that such a strategy can be implemented towards the production of other commodity chemicals including organic acids. In an effort to assemble cellulosome-inspired multi-enzyme complexes on the surface of a bacterium, Wieczorek and Martin engineered a strain of L. lactis to anchor mini-scaffolds on the cell surface [123]. While several bacterial species non-covalently anchor cellulosomes to the cell surface by means of S-layer homologous domains, other organisms such as R. flavefaciens display cellulosomes by covalently anchoring them to the cell wall by sortase. Therefore, the authors in this study fused fragments of C. thermocellum CipA scaffold with a C-terminal LPXTG-containing anchor motif from Streptococcus pyogenes M6 protein, resulting in their successful surface-display. By fusing the scaffolds with the export-specific reporter, S.aureus nuclease NucA, the authors were able to easily detect them in the extracellular medium. Fusion of E. coli β-glucuronidase UidA with the dockerin from major C. thermocellum cellulosomal enzyme CelS, resulted in its successful targeting to the surface-displayed scaffolds. While the assembled complexes were not cellulolytic, the investigation yielded insights into parameters affecting secretion and anchoring of the recombinant scaffolds, including the observation that scaffold size was not a significant bottleneck in display efficiency. The strain used was deficient in its major extracellular housekeeping protease HtrA, which has been demonstrated to be responsible for the degradation of secreted recombinant proteins. In a subsequent study, the authors fused type 1 and type 2 cohesins to generate scaffold chimeras capable of binding UidA and E. coli β-galactosidase LacZ fused with type 1 and type 2 dockerins (unpublished data). This system yielded novel insights into the assembly of displayed complexes, suggesting that enzyme size and position relative to the cell surface may play a role in determining the overall net enzymatic profile of the displayed complexes.
3.4.3. Anchoring recombinant cellulosomes on the cell surface of B. subtilis
The interest in B. subtilis as a potential candidate for the consolidated bioprocessing of cellulosic substrates into chemicals and fuels resulted in the development of recombinant cellulosome systems in this organism. The attractiveness of this host is compounded by several characteristics including its ability to metabolize C5 and C6 sugars as well as its natural ability to uptake long-chain cellodextrins. Anderson and colleagues used a system similar to the Martin group\'s by employing the sortase-mediated anchoring of proteins on the cell surface [124]. This group initially demonstrated proof of concept by displaying a single enzyme, Cel8A, and subsequently went on to display cohesin domains capable of interacting with an appropriate Cel8A-dockerin fusion. It was observed that proteolytic degradation of the displayed enzymes resulted in an 80% decrease in activity after only 6 hours, an effect hypothesized to result from the presence of the extracellular housekeeping protease WprA. Inserting this system into a WprA- strain resulted in a significant reduction in the observed proteolysis of the enzymes. The most complex artificial cellulosome generated by this group included a surface-anchored chimeric scaffold containing three divergent cohesins and a CBD. Incubation of cells with enzyme-dockerin fusions purified from E. coli resulted in the assembly of functional minicellulosomes on the cell surface. Soon afterwards, the Zhang group reported the engineering of a scaffold-displaying B. subtilis strain capable of binding three enzymes and the subsequent assembly of an artificial cellulosome on the cell surface [125]. These authors investigated the effect of the CEM ternary complex by comparing a cell-bound artificial cellulosome, a cell-free artificial cellulosome, and a commercial fungal cellulose mixture. Comparative enzyme assays were conducted on the recalcitrant substrate Avicel, as well as amorphous cellulose. When comparing the activity of cell-bound cellulosomes vs. cell-free cellulosomes, a larger significant increase in CEM synergy on Avicel as opposed to amorphous cellulose was observed in the cell-displayed constructs. The authors suggest this effect to be due to larger product inhibition at the boundary layer when active on crystalline cellulose. Since EGL demonstrates higher hydrolysis activity on amorphous cellulose, and CBH is more sensitive to product inhibition, the observed results suggest that the benefits of anchoring cellulosomes on the cell surface are a necessary component of a CBP-capable organism. In Table 1, successfully generated recombinant cellulosome components are listed according to host organism and assembly strategy.
Strategies, organisms and successfully assembled recombinant cellulosomes
4. Conclusion
Recent decades have yielded significant advances in the engineering of non-cellulolytic organisms towards the degradation of cellulosic substrates into fermentable sugars. The recombinant production of cellulases is both a necessary and effective means to both characterize and utilize non-native enzymes in a host organism of choice. In addition, the recalcitrance of crystalline cellulose and complexity of hemicellulose requires multiple enzymes working together to fully achieve this bioconversion process. The potential of custom-designed recombinant cellulosomes to optimize ratio and positioning of enzymes within artificial complexes contribute to this goal. Still, significant advances are necessary in order for the cost-effective transformation of cellulose into valuable commodity chemicals such as bioethanol, non-biofuel hydrocarbons, and organic acids to become an industrial standard. For example, of significant importance is the optimizing of secretion and anchoring mechanisms in host organisms, two factors which can prove to be bottlenecks in the engineering process. Indeed, the native metabolic diversity of microbes designed to utilize cellulose as an energy source, as well as the advent of synthetic biology through which non-native and novel pathways can be introduced into these organisms, suggest that the bioconversion of cellulosic substrates into valuable chemicals is not so far from reach. Constructing more efficient recombinant cellulases, as well as the assembly of cellulosomes with complex architectures inspired by bacteria such as R. Flavifaciens and A. cellulolyticus, are possible avenues to explore in this field. With the inevitable depletion of reserves of conventional energy sources such as petroleum and other fossil fuels, it becomes more evident that cellulosic biomass is not only an attractive source for the production of alternative fuel sources, but may soon become a necessary one.
\n',keywords:null,chapterPDFUrl:"https://cdn.intechopen.com/pdfs/45630.pdf",chapterXML:"https://mts.intechopen.com/source/xml/45630.xml",downloadPdfUrl:"/chapter/pdf-download/45630",previewPdfUrl:"/chapter/pdf-preview/45630",totalDownloads:3259,totalViews:362,totalCrossrefCites:0,totalDimensionsCites:1,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:9,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"November 4th 2011",dateReviewed:"October 9th 2012",datePrePublished:null,datePublished:"August 29th 2013",dateFinished:"August 28th 2013",readingETA:"0",abstract:null,reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/45630",risUrl:"/chapter/ris/45630",book:{id:"3174",slug:"cellulose-biomass-conversion"},signatures:"Andrew S. Wieczorek, Damien Biot-Pelletier and Vincent J.J. Martin",authors:[{id:"139158",title:"Dr",name:null,middleName:null,surname:"Martin",fullName:"Martin",slug:"martin",email:"vmartin@alcor.concordia.ca",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Cell surface-anchored and secreted recombinant cellulase systems",level:"1"},{id:"sec_2_2",title:"2.1. Expression of cellulases in yeast",level:"2"},{id:"sec_2_3",title:"2.1.1. Recombinant cellulase expression in Saccharomyces cerevisiae ",level:"3"},{id:"sec_3_3",title:"2.1.2. Recombinant cellulase expression in other yeast species",level:"3"},{id:"sec_5_2",title:"2.2. Expression of cellulases in bacteria",level:"2"},{id:"sec_5_3",title:"2.2.1. Recombinant cellulase expression in enteric bacteria",level:"3"},{id:"sec_6_3",title:"2.2.2. Recombinant cellulase expression in Zymomonas mobilis ",level:"3"},{id:"sec_7_3",title:"2.2.3. Recombinant cellulase expression in other bacterial hosts",level:"3"},{id:"sec_9_2",title:"2.3. Expression of cellulases in fungi ",level:"2"},{id:"sec_11",title:"3. Recombinant cellulosomes ",level:"1"},{id:"sec_11_2",title:"3.1. Nature’s building blocks for engineering recombinant cellulosomes",level:"2"},{id:"sec_12_2",title:"3.2. In vitro assembly of recombinant cellulosomes",level:"2"},{id:"sec_12_3",title:"3.2.1. Expression of cellulosome components in E. coli",level:"3"},{id:"sec_13_3",title:"3.2.2. Expression of cellulosome components in B. subtilis",level:"3"},{id:"sec_15_2",title:"3.3. In vivo secretion and assembly of recombinant cellulosomes",level:"2"},{id:"sec_15_3",title:"3.3.1. Secretion of recombinant cellulosomes by B. subtilis",level:"3"},{id:"sec_16_3",title:"3.3.2. Secretion of recombinant cellulosomes by C. acetobutylicum",level:"3"},{id:"sec_18_2",title:"3.4. In vivo surface-anchoring of recombinant cellulosomes",level:"2"},{id:"sec_18_3",title:"3.4.1. Anchoring recombinant cellulosomes on the cell surface of S. cerevisiae",level:"3"},{id:"sec_19_3",title:"3.4.2. Anchoring recombinant cellulosomes on the cell surface of L. lactis",level:"3"},{id:"sec_20_3",title:"Table 1.",level:"3"},{id:"sec_23",title:"4. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'KlesovABiochemistry and enzymology of cellulose hydrolysis. Biokhimiya. 1991551295318'},{id:"B2",body:'TeeriTCrystalline cellulose degradation: new insights into the function of cellobiohydrolases. Trends Biotechnol. 1997155160167'},{id:"B3",body:'WatanabeHTokudaGCellulolytic systems in insectsAnnu Rev Entomol. 201055609'},{id:"B4",body:'BayerE. ABelaichJ. 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\n
1. Introduction
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As early as the 1970s, Maxwell revealed that electromagnetic waves can carry momentum in his famous electromagnetic field theory. When electromagnetic waves are applied to objects, they will transmit momentum. Therefore, electromagnetic waves can exert force on objects, and then the concept of electromagnetic force is proposed [1]. Until the beginning of the twentieth century, Einstein proposed the concept of photonic quantum, which believes that light is composed of a group of photons with both mass and momentum. When light is irradiated on the surface of the object, it can cause changes in the photon momentum to produce radiation pressure on the object due to the scattering and absorption of light. Subsequently, Lebedev, Nichol, and Hull first demonstrated the existence of radiation pressure experimentally. The experiment used arc lamps and torsion scales to observe the effect of light in the macroscopic physical world. However, the light produced by the arc lamp is very weak and difficult to practically apply. Until 1960, the invention of the laser provided a high-intensity optical source for studying optical force, which greatly promoted the application of optical manipulation. Arthur Ashkin, a scientist at Bell Experiments in the United States, first used the radiation pressure generated by the laser beam to push tiny particles in the liquid environment [2] and then used two opposing laser beams to capture microparticles and even atoms. However, the experimental setup used in the dual-beam capture method is too complex and can only limit microparticles in a two-dimensional plane. Scientists hope to use a single laser to achieve three-dimensional trapping of microparticles. To this end, in 1986, Ashkin et al. used a high-numerical-aperture objective to focus a single laser to trap microparticles and named the technology “single beam gradient force trap” [3]. A year later, Ashkin et al. continued to improve this technology and achieved optical trapping and manipulation of tiny bacteria and viruses. They officially named the technology “optical tweezers” [3]. Compared with traditional macro-mechanical tweezers, the optical tweezers have the advantages of noncontact and no damage and can perform high-precision manipulation of microscopic particles. Therefore, since the birth of the optical tweezer technology, it has played an important role in the fields of biomedicine and physical chemistry.
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1.1 Traditional optical tweezers
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1.1.1 Basic principles
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The core component of the traditional optical tweezers is a highly focused beam, as shown in \nFigure 1a\n [4]. When the incident laser (usually a near-infrared laser with a wavelength of 1064 nm) is focused by a high-numerical-aperture objective lens, the microparticles in the liquid environment will be exposed to optical force near the focus. This force is derived from the momentum transfer effect between light and particles. Specifically, the optical forces are divided into two components: one component along the direction of the optical gradient, called the optical gradient force, which is caused by the microparticles being in a nonuniform optical field, and the optical gradient force, which drives the particles to the area where the optical intensity is greatest; another component along the direction of optical propagation, called optical scattering force, is caused by the scattering and absorption of particles, and the optical scattering force causes the microparticles to move along the direction of optical propagation. By modulating the focused beam, the magnitude of two forces can be varied to achieve different functions such as capture, acceleration, and rotation of the microparticles. For traditional optical tweezers to construct a stable trap, it is necessary to focus the incident laser with a high-numerical-aperture (generally NA = 1.0~1.4) objective lens. The resulting optical gradient force is greater than the optical scattering force, so the microparticles or the cells can be stably trapped in the focus of light [5].
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Figure 1.
Schematic diagram of the traditional optical tweezers. (a) A single microparticle is trapped to the focused spot of a laser beam by gradient force and scattering force to [4]. (b) A simple harmonic oscillator model for the optical trapping of the microparticle.
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The model in which the object is trapped by the optical tweezers can be equivalent to a simple oscillator, as shown in \nFigure 1b\n. The magnitude of the object’s received optical force (F) is proportional to the object’s distance from the focus (d), which is
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\n\n\n\nF\n=\n−\nkd\n\n\n\nE1
\n
where the constant k represents the spring constant of the spring oscillator and the strength of the trap. Therefore, when we know the motion of an object in a trap, the magnitude of the optical force can be calculated by Formula 1. However, in the more general case, we want to quantitatively analyze the optical force when the unknown object motions and then other optical theories are needed. The theoretical analysis of optical tweezers needs to be determined according to the size of the object, specifically divided into three cases: first, when the radius (R) of the particle is much larger than the wavelength (λ) of the incident light, then a simple geometric optical method can be used to analyze the force of the object; second, if the size of the particle is much smaller than the wavelength of the incident light, the particle can be equivalent to the dipole in the electric field, and a dipole approximation model is needed; and third, if the size of the particles is close to the wavelength of the light, the situation becomes complicated, and the Maxwell equation is needed to solve the problem.
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We first analyze the Rayleigh nanoparticle (R <<λ). At this time, the nanoparticle can be regarded as a dipole in a nonuniform electromagnetic field, and the optical gradient force (\nF\n\n\ngrad\n) of the dipole in the electromagnetic field can be expressed as
where α is the polarizability of the dipole, \nE\n is the electric field, parentheses indicate the time average, and \n|E\n\n\n\n2\n\n\n\n|\n is proportional to the intensity of the electromagnetic field. It can be seen from Formula 2 that the direction of the optical gradient force \nF\n\n\ngrad\n is along the direction of the optical intensity gradient. Thus, for a highly concentrated beam, the particles are drawn to the focus of the spot. Here, the polarizability α is a crucial parameter that directly determines the intensity of the interaction of light with object. For spherical nanoparticles, α can be expressed as [6]
where k = 2πn/λ is the scalar of the incident light wave vector, ε is the dielectric constant of the particle, ε0\n is the dielectric constant of the vacuum, α\n0 is the quasi-static polarizability of the nanoparticle, and α\n0 can be given by the Clausius-Mossotti relation [6]:
The radiation pressure (\nF\n\n\nrad\n) is produced by the scattering and absorption of light by the surface of the particles, which can be expressed as [7]
where n is the refractive index of the surrounding environment, c is the speed of light in the vacuum, and 〈P〉 is the time-averaged Poynting vector, which can be expressed as
The σ in Formula 6 reflects the characteristics of the nanoparticle, which indicates the extinction cross section of the nanoparticle, including the scattering cross section (σ\nscat) and the absorption cross section (σ\nabs), and σ is determined by the following formula [8]:
where \n\n\nα\n\n′\n′\n\n\n\n is the imaginary part of the particle polarizability α, which represents the absorption of light by the particles. For transparent media particles, this term is approximately equal to zero and can be ignored. It can be seen from Formula 5 that the direction of the optical scattering force coincides with the direction of the glass booth vector, that is, the direction in which the optical scattering force propagates along the light. When \nF\n\n\ngrad >\nF\n\n\nrad\n, the trapping of particles can be achieved.
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The dipole approximation model is only applicable to spherical nanoparticles. When the shape of the captured object is irregular or the size is the same magnitude as the wavelength, it needs to be solved from the most basic Maxwell equations using simulation software. This method is based on the Maxwell stress tensor integral of the surface S of the object, as defined below:
where \n\nE\n\n\n and \n\nH\n\n are the electric field vector and the magnetic flux vector in the electromagnetic field, \n\n\nE\n∗\n\n\n and \n\n\nH\n∗\n\n\n are complex conjugates, \nI\n is an isotropic tensor, and ε and μ represent the dielectric constant and magnetic permeability, respectively. After calculating the optical force, the torque of the object can also be calculated by the following formula:
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\n\n\n\nT\n=\n∫\nr\np\n×\nd\nF\np\n,\n\n\n\nE10
\n
where \n\nd\nF\np\n\n represents the unit force at the point of action p and \n\nr\np\n\n is the position vector from the center of the object to the point of action p.
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1.1.2 Applications of the optical tweezers
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Professor Ashkin, the pioneer of optical tweezers, predicted that optical tweezers as the manipulation technology of tiny particles will be widely used in the research of molecular biology, cell biology, and mesoscopic physics, especially to promote the development of many interdisciplinary subjects [9]. As an example, we will introduce some of the applications of the optical tweezers in the following aspects:
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1.1.2.1 Capture, separation, and assembly of microparticles and cells
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The invention of optical tweezers was used to capture and manipulate tiny particles such as polystyrene microspheres, biological cells, viruses, and bacteria [12]. By capturing these tiny particles, the Brownian motion of particles can be overcome and fixed in the field of the microscope for the researcher to observe and detect. When the particles are stably captured, they can be moved to a specific position and arranged in a regular pattern, which is applied to the ordered assembly of particles and cell arrays (as shown in \nFigure 2a\n), giving it a specific function. Further, by measuring the mechanical properties of particles and cell array, the interaction between the particles or cells can be studied. In addition, since different types of particles and cells are affected by the magnitude and direction of optical force, separation and screening of particles and cells can be achieved. With the maturity of optical tweezer technology, the system of optical tweezers is gradually combined with Raman technology, fluorescence technology [13], confocal technology, and femtosecond laser technology and achieves real-time detection of captured targets, which will enrich the applications of optical tweezers in cell biology and colloidal physics.
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Figure 2.
Several application examples of traditional optical tweezers. (a) Order and assemble microparticles and cells. (b) Study the interaction of nucleic acid molecules using micron media balls as handles [10]. (c) Rotating the microspheres using a vortex beam [11]. (d) Stretching human red blood cells using a micron media ball as a handle.
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1.1.2.2 Study of optical tweezers and single molecules
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The optical technology has a high mechanical resolution (10−12–10−15 N), which is sufficient for the study of individual biomacromolecules. For example, the basic laws of life movement are explained by measuring the physical forces such as the tiny force of biological single molecule and the motion step size. Optical tweezer technology has become an indispensable tool for quantitatively studying life processes and transforming life activities. Since the diameter of biomolecules is generally between 1 and 10 nanometers, the optical tweezer system cannot directly observe and manipulate. In order to see a single molecule, it is necessary to combine fluorescence imaging technology; in order to manipulate a single molecule, it is necessary to connect the molecule to the microsphere and indirectly manipulate and measure by using the small microsphere as the “handle” of the manipulation. For example, the two ends of the DNA molecular chain are, respectively, connected to two microspheres, and the microspheres are manipulated by a double-beam tweezers to stretch the DNA molecular chain and measure its elastic properties (as shown in \nFigure 2b\n) [10]. By rotating the two microspheres in the opposite direction, the binding force of the DNA molecular chain can be calculated. Using similar methods, researchers can also study the properties of various biomacromolecules: RNA transcription, kinesin movement, the role of polymerases, etc. These are the basic processes of life activities. Its high-precision measurement can reveal the basic laws of life activities and lay the foundation for the research and application of biomedicine.
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1.1.2.3 Optical rotator
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The optical rotator is a branch of the optical tweezers that not only captures the microparticles but also allows the angular rotation of the microparticles as shown in \nFigure 2c\n [11]. This technique is based on the moment applied by the angular momentum of the light to the object. In order to achieve the rotation of the particles, the optical rotator requires a special beam of angular momentum, such as a Laguerre-Gauss beam [14]. Rotating particles or cells are used in many fields, such as rotating a tiny mechanical motor in a liquid environment to control the movement of local water flow. In addition, by rotating living cells, it can be imaged at various angles, which is beneficial to observe the full three-dimensional appearance of cells.
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1.1.2.4 Optical stretchers
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Stretching cells can study the elasticity of cell membranes, and the elasticity of cell membranes is closely related to many cellular diseases and can be used to reflect the activity of cells and even the health of the human body. There are many optical stretching methods based on optical tweezers, such as direct stretching of double-beam tweezers, stretching by microsphere handle, time-division multiplexed stretching, and so on. The method based on the microsphere handle-stretching method is more commonly used because of the high measurement precision. The method is shown in \nFigure 2d\n: two microspheres are adhered to the cell surface by chemical coupling, and then the microspheres are controlled to move in opposite directions by the tweezers. At this time, the cell membrane is stretched by shearing force. By recording the shape variables of the cells and measuring the force of stretching the microspheres, physical parameters such as the elastic modulus of the cell membrane can be calculated.
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1.2 Holographic optical tweezers
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1.2.1 Basic principles
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Traditional optical tweezers based on single beam can only capture and manipulate one or a few particles at a time. However, researchers want to improve the efficiency of capture, such as controlling multiple particles at the same time. Based on this goal, scientists invented holographic optical tweezers. The core component of holographic optical tweezers is a hologram element: an interference pattern formed by recording the object light and reference light through the film. The wave front can be adjusted by holographic elements to construct a light field with a specific function. The holographic optical tweezers were firstly invented in 1998 by Professor Grier of the University of Chicago and his collaborators [15]. They used a holographic element (diffraction grating) to split the collimated single laser beam into multiple independent beams, and then an array of grating is formed by focusing the lens to capture a large number of microparticles. The earliest holographic elements were prepared by coherent-optical interferometry, but the holographic elements obtained by this method have low diffraction efficiency and poor versatility, and thus this method has not been widely used. In order to improve diffraction efficiency and applicability, conventional holographic elements are often composed of spatial light modulators. The spatial light modulators include liquid crystal spatial light modulators, acousto-optic modulators, and digital microlens arrays. The spatial light modulator is controlled by a computer, and each focused beam can be individually controlled by changing the hologram element so that the formed trap well can be dynamically changed. Such holographic optical tweezers not only capture a plurality of microparticles at the same time but also control the movement of each microparticle to be arranged in different shapes, thereby achieving ordered assembly of the microparticles.
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1.2.2 Applications of the holographic optical tweezers
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As an emerging optical technology, holographic optical tweezers can trap and manipulate a large number of particles, showing great application prospects in the fields of particle assembly and construction of three-dimensional cell microstructure (\nFigure 3\n). For example, Glen R. Kirkham et al. of the United Kingdom used holographic optical tweezers to assemble one-, two-, and three-dimensional embryonic stem cell array structures (as shown in \nFigure 4\n) to provide a new means to study the directed differentiation of stem cells [16]. Moreover, Jesacher and his colleagues from Austria regulated the amplitude and phase of the incident light field through a liquid crystal spatial light modulator, which not only realized trapping potential wells of special shapes such as line, cross, circle, and rectangle but also controlled the microparticle movement along a specific path. In addition, holographic optical tweezer technology can also produce beams with special modes, such as Bessel beams, Laguerre-Gauss beams, and Airy beams [18]. These special-mode beams have peculiar phase distribution and propagation characteristics and can generate trapped potential wells with special functions, such as rotating particles with a Laguerre-Gauss beam, which can be used to construct micro- and nano-motors and study the transfer of orbital angular momentum; Airy beam or Bessel beam can be used to transport particles for sorting different types of particles and cells.
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Figure 3.
Bright-field optical micrographs and confocal fluorescence micrographs of one-, two-, and three-dimensional microarray structures of embryonic stem cells assembled by holographic optical tweezers [16].
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Figure 4.
The basic principle of the fiber-based optical tweezers. (a) Schematic diagram of the optical gradient force (Fg) and scattering force (Fs) applied to the microparticles by the fiber-based optical tweezers. (b) Simulation of electric field intensity distribution of the fiber-based optical tweezers. (c) A chain of yeast cells was trapped by the fiber-based optical tweezers [17].
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1.3 Fiber-based optical tweezers
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1.3.1 Basic principles
\n
Due to the low integration of conventional optical tweezer systems, it is difficult to manipulate particles located in a narrow position, such as particles inside a microfluidic channel or red blood cells in a blood vessel. The newly developed fiber-based optical tweezers are promising candidates because of its compact structure and flexible operation, which can overcome the problems of traditional optical tweezers [19]. Fiber-based optical tweezers use the output light from the end face of the fiber to achieve particle capture and manipulation, as shown in \nFigure 5a\n. When the laser beam passes into the fiber, it converges through the end of fiber and form a highly focused beam. The microparticles located near the tip of the fiber will be captured by the longitudinal gradient force onto the optical axis of the fiber and then captured by the lateral gradient force at the focus of the emitted light or move along the optical axis under the action of optical scattering force. For fiber-based optical tweezers, the distribution of the exiting light field depends on the shape of the fiber tip, which is a highly focused beam, to create a three-dimensional trapping potential. Currently, the tip of the fiber-based optical tweezers is generally designed as a parabolic, spherical, or conical structure. Different shapes of fiber tip can be prepared by physical polishing, heating stretching, chemical etching, and femtosecond laser processing. By changing the physical parameters of the preparation method, such as temperature, speed, time, etc., the shape and size of the fiber tip can be controlled to achieve different functions. \nFigure 5b\n shows the output light field distribution of a typical tapered fiber. It can be seen that the light is concentrated at the front end of fiber so that the cells can be trapped on the axis of the front end of the fiber and arranged into an ordered structure, as shown in \nFigure 5c\n [17].
\n
Figure 5.
This schematic shows a versatile fiber-based optical tweezers: number 1 indicates the capture, transport, and sorting of cells, number 2 indicates the optical stretching and deformation of cells, and numbers 3 indicates the optical rotation of cells.
\n
\n
\n
1.3.2 Application of fiber-based optical tweezers
\n
Since the fiber-based optical tweezers have the advantages of simple fabrication, flexible operation, compact structure, and easy integration, it has applications in many fields. For example, Xin et al. used a flame heating and melting taper to prepare a fiber-based optical tweezers with a tapered tip, which enables the capture of submicron-sized polystyrene particles and E. coli cells [20, 21]. Xu et al. realized the rotation of single silver nanowires using two tapered fibers, which provide a controlled and optical method for assembling plasmonic nanostructures [22]. Fiber-based optical tweezers will be developed in the direction of high integration and multifunctionality to adapt to lab-on-a-chip and in vivo requirements. In the future, the fiber-based optical tweezers may integrate multiple functions on a single-fiber probe, as shown in \nFigure 6\n, such as simultaneously capturing, transporting, sorting, stretching, deforming, and rotating various cells and pathogens in the microfluidics or living blood.
\n
Figure 6.
Slot waveguide optical tweezers. (a) Schematic diagram of the optical gradient force and scattering force of nanoparticles in the slot waveguide. (b) A simulation result of the light intensity distribution of the slot waveguide in an aqueous environment. (c) An electron scanning micrograph of a waveguide having a slit of 100 nm. (d) The slot waveguide captures a large number of polystyrene particles of 75 nm in diameter in the water flow [23].
\n
\n
\n
\n
1.4 Nano-optical tweezers
\n
\n
1.4.1 Planar waveguide optical tweezers
\n
When the light is transmitted in the waveguide, an evanescent wave is generated on the surface of the waveguide due to the total reflection. The evanescent wave is limited to a near-field range of 100 nanometers from the surface of the waveguide. When a nanoparticle enters the evanescent wave, the gradient of the light intensity changes greatly in the direction perpendicular to the waveguide, so the nanoparticles will be trapped on the surface of the waveguide by a strong optical gradient force. In the direction of light propagation, the evanescent wave can be considered to be uniformly distributed. Therefore, there is no optical gravity force in this direction. Only the optical scattering force exists. The nanoparticles move along the direction of light propagation due to the optical scattering force. Therefore, planar waveguide optical tweezers are often used for the transport of nanoparticles. Moreover, since the optical waveguide device is easily integrated into the microfluidic chip, the planar waveguide optical tweezers play an important role in the field of microfluidics. Current planar waveguide optical tweezers can be classified into three types: rectangular waveguide optical tweezers, slot waveguide optical tweezers, and nanofiber waveguide optical tweezers.
\n
The manipulation of microparticles by a rectangular waveguide optical tweezers was first implemented by Kawata et al. [5]. They use rectangular waveguides to perform noncontact optical transport of different sizes of microparticles. This method can deliver cells or drugs over long distances. After this groundbreaking work, more and more researchers have entered this field and designed rectangular waveguides with different structures for transporting metal particles, media particles, microbial cells, etc. [5].
\n
Since the evanescent wave of the rectangular waveguide has limited light confinement, it is challenging for the rectangular waveguide to capture particles and biomolecules below 100 nm. To solve this limitation, the researchers developed slot waveguide nanotweezers [23]. The slot waveguide is an air slit having a width of nanometers by photolithography or electron beam etching. The large refractive index contrast between low refractive index slot and high refractive index waveguide material makes the light energy highly confined in the slot region, which produces a strong optical gradient force and scattering force on the nanoparticles entering the slot. Using this property, Yang et al. achieved capture and transport of polystyrene particles and DNA molecules with sizes below 100 nanometers (as shown in \nFigure 7\n) [23].
\n
Figure 7.
Photonic crystal optical tweezers. (a) Schematic representation of a single-dimensional photonic crystal resonator capturing a single nanoparticle [24]. (b) Schematic representation of a two-dimensional photonic crystal resonator capturing a single E. coli [25].
\n
A common problem with rectangular waveguide optical tweezers and slot waveguide optical tweezers is that they must be fixed on the substrate, making it difficult to operate. The emerging nanofiber waveguide optical tweezers can solve this problem. Li et al. used fibers with a diameter of 500–700 nm to achieve stable trap, bidirectional transport, optical separation, and controlled release of nanoparticles and micro-pathogens in microfluidics [26, 27]. The nanofiber waveguide optical tweezers have the advantages of low cost, production, and large control range and have important research value and application prospects in cell transportation, drug delivery, and particle collection.
\n
\n
\n
1.4.2 Photonic crystal optical tweezers
\n
Optical tweezers based on rectangular waveguides, slot waveguides, and nanofiber waveguides can only move particles along the waveguide surface but cannot be used to stably trap nanoparticles. In order to stably capture the nanoparticles, a photonic crystal optical tweezers were developed. The photonic crystal optical tweezers are based on one- or two-dimensional photonic crystal resonator structures (as shown in \nFigure 8\n) [24, 25]. When the laser that satisfies the wavelength matching condition is coupled into the photonic crystal resonator, static interference will occur in the cavity. With the resonance effect, the intensity of the light is greatly enhanced, and the size of the light spot is strongly suppressed, thereby enhancing the optical force of nanoparticles. Based on this principle, Erickson and Mandal et al. achieved stable capture and controlled release of nano-objects such as polystyrene particles, semiconductor quantum dots, and serum protein molecules in a liquid environment [30]. In addition, this method can also be used to study the angular rotation of silver nanowires or carbon nanotubes [31].
\n
Figure 8.
Plasmon optical tweezers. (a) Schematic diagram of a metal film having nanopores. (b) Schematic diagram of magnified metal nanopore capture nanoparticles. (c) SEM image of the metal nano-antenna structure and motion trajectory after the nanoparticles are captured. (d) Schematic representation of metal nano-antenna structures [28]. (e) SEM image of a metal nano-bowtie structure. (f) Schematic diagram of metal bow nanostructure [29].
\n
\n
\n
1.4.3 Plasmon optical tweezers
\n
Plasmon is a near-field electromagnetic wave formed by the resonance of free electrons on a metal surface and incident photons. Under such resonance conditions, the energy of the electromagnetic field will be converted into the collective vibrational energy of the free electrons on the metal surface, thereby forming a special electromagnetic field: the light is confined to the sub-wavelength of the metal surface and greatly enhanced. The effect is called the plasmon effect. Since the plasmon effect localizes the light in the near-field range of the nanometer order, it is widely used in the fields of fluorescence signal enhancement, near-field super-resolution imaging, high-density optical storage, integrated optical circuits, etc. [32]. In recent years, the plasmon effect has also been applied in the field of optical trapping and manipulation. The plasmon effect is divided into two types: surface plasmon resonance (SPR) and local surface plasmon resonance (LSPR), both of which can be used to enhance optical force. Researchers used a prismatic total internal reflection to couple incident light into a metal micro-disk on the substrate, which will increase the optical force of the particle by two orders of magnitude and realize the capture of the microparticle. However, the SPR-based optical tweezers can only enhance the optical force of the particle in a two-dimensional plane. Therefore, researchers have proposed an LSPR-based nano-optical tweezers to enhance the optical force of the nanoparticle in three dimensions, including metal nanopores (\nFigure 8a\n,\nb\n), metal nano-antennas (\nFigure 8c\n,\nd\n) [28], metal nano-bows (\nFigure 8e\n,\nf\n) [29], and metal nano-double holes [33]. By using these nano-optical tweezers to achieve trapping of various nanoparticles, such as polystyrene particles, protein molecules, gold particles, micro-pathogenic bacteria, and so on.
\n
\n
\n
\n
\n
2. Conclusions
\n
The noncontact and noninvasive optical trapping and manipulation of microparticles, cells, and biomolecules in liquid environments has broad application prospect in the fields of biomedicine and nanomaterial science [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47]. Traditional optical tweezers and holographic optical tweezers play an important role in the study of microscale optical manipulation. However, in the rapid development of nanoscience, traditional optical tweezers and holographic optical tweezers are difficult to adapt integration and nano-precision requirements due to the large volume and diffraction limitations. The developed nano-optical manipulation techniques, such as planar waveguides, plasmon optical tweezers, and photonic crystal resonators, can overcome the problem of difficult integration and diffraction limitations of conventional optical tweezers and holographic optical tweezers, which hold great promise in biophotonic and biomedical applications.
\n
\n
Acknowledgments
\n
This work was supported by the National Natural Science Foundation of China (No. 11774135, 11874183, and 61827822).
\n
Conflict of interest
The authors declare no competing financial interests.
\n',keywords:"optical tweezers, optical force, optical manipulation, biophotonics, biotechnology",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/66782.pdf",chapterXML:"https://mts.intechopen.com/source/xml/66782.xml",downloadPdfUrl:"/chapter/pdf-download/66782",previewPdfUrl:"/chapter/pdf-preview/66782",totalDownloads:1205,totalViews:0,totalCrossrefCites:0,dateSubmitted:"February 17th 2019",dateReviewed:"March 25th 2019",datePrePublished:"April 28th 2019",datePublished:"May 6th 2020",dateFinished:"April 18th 2019",readingETA:"0",abstract:"Three-dimensional optical manipulation of microparticles, cells, and biomolecules in a noncontact and noninvasive manner is crucial for biophotonic, nanophotonic, and biomedical fields. Optical tweezers, as a standard optical manipulation technique, have some limitations in precise manipulation of micro-objects in microfluidics and in vivo because of their bulky lens system and limited penetration depth. Moreover, when applied for trapping nanoscale objects, especially with sizes smaller than 100 nm, the strength of optical tweezers becomes significantly weak due to the diffraction limit of light. The emerging near-field methods, such as plasmon tweezers and photonic crystal resonators, have enabled surpassing of the diffraction limit. However, these methods msay lead to local heating effects that will damage the biological specimens and reduce the trapping stability. Furthermore, the available near-field techniques rely on complex nanostructures fixed on substrates, which are usually used for 2D manipulation. The optical tweezers are of great potential for the applications including nanostructure assembly, cancer cell sorting, targeted drug delivery, single-molecule studies, and biosensing.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/66782",risUrl:"/chapter/ris/66782",signatures:"Zhiyong Gong and Yuchao Li",book:{id:"7714",type:"book",title:"Emerging Micro",subtitle:"and Nanotechnologies",fullTitle:"Emerging Micro - and Nanotechnologies",slug:"emerging-micro-and-nanotechnologies",publishedDate:"May 6th 2020",bookSignature:"Ruby Srivastava",coverURL:"https://cdn.intechopen.com/books/images_new/7714.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-78985-598-2",printIsbn:"978-1-78985-597-5",pdfIsbn:"978-1-78985-100-7",isAvailableForWebshopOrdering:!0,editors:[{id:"185788",title:"Dr.",name:"Ruby",middleName:null,surname:"Srivastava",slug:"ruby-srivastava",fullName:"Ruby Srivastava"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"295828",title:"Associate Prof.",name:"Yuchao",middleName:null,surname:"Li",fullName:"Yuchao Li",slug:"yuchao-li",email:"liyuchao@jnu.edu.cn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"298889",title:"MSc.",name:"Zhiyong",middleName:null,surname:"Gong",fullName:"Zhiyong Gong",slug:"zhiyong-gong",email:"375967138@qq.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Traditional optical tweezers",level:"2"},{id:"sec_1_3",title:"1.1.1 Basic principles",level:"3"},{id:"sec_2_3",title:"1.1.2 Applications of the optical tweezers",level:"3"},{id:"sec_2_4",title:"1.1.2.1 Capture, separation, and assembly of microparticles and cells",level:"4"},{id:"sec_3_4",title:"1.1.2.2 Study of optical tweezers and single molecules",level:"4"},{id:"sec_4_4",title:"1.1.2.3 Optical rotator",level:"4"},{id:"sec_5_4",title:"1.1.2.4 Optical stretchers",level:"4"},{id:"sec_8_2",title:"1.2 Holographic optical tweezers",level:"2"},{id:"sec_8_3",title:"1.2.1 Basic principles",level:"3"},{id:"sec_9_3",title:"1.2.2 Applications of the holographic optical tweezers",level:"3"},{id:"sec_11_2",title:"1.3 Fiber-based optical tweezers",level:"2"},{id:"sec_11_3",title:"1.3.1 Basic principles",level:"3"},{id:"sec_12_3",title:"1.3.2 Application of fiber-based optical tweezers",level:"3"},{id:"sec_14_2",title:"1.4 Nano-optical tweezers",level:"2"},{id:"sec_14_3",title:"1.4.1 Planar waveguide optical tweezers",level:"3"},{id:"sec_15_3",title:"1.4.2 Photonic crystal optical tweezers",level:"3"},{id:"sec_16_3",title:"1.4.3 Plasmon optical tweezers",level:"3"},{id:"sec_19",title:"2. 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DOI: 10.1021/nl203719v\n'},{id:"B43",body:'\nShoji T, Tsuboi Y. Plasmonic optical tweezers toward molecular manipulation: Tailoring plasmonic nanostructure, light source, and resonant trapping. Journal of Physical Chemistry Letters. 2014;5:2957-2967. DOI: 10.1021/jz501231h\n'},{id:"B44",body:'\nYu XC et al. Single nanoparticle detection and sizing using a nanofiber pair in an aqueous environment. Advanced Materials. 2014;26:7462-7467. DOI: 10.1002/adma.201402085\n'},{id:"B45",body:'\nNdukaife JC, Kildishev AV, Nnanna AGA, Shalaev VM, Wereley ST, Boltasseva A. Long-range and rapid transport of individual nano-objects by a hybrid electrothermoplasmonic nanotweezer. Nature Nanotechnology. 2016;11:53-59. DOI: 10.1038/nnano.2015.248\n'},{id:"B46",body:'\nDholakia K, Reece P, Gu M. Optical micromanipulation. Chemical Society Reviews. 2008;37:42-55. DOI: 10.1039/B512471A\n'},{id:"B47",body:'\nJuan ML, Righini M, Quidant R. Plasmon nano-optical tweezers. Nature Photonics. 2011;5:349-356. DOI: 10.1038/nphoton.2011.56\n'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Zhiyong Gong",address:null,affiliation:'
Institute of Nanophotonics, Jinan University, Guangzhou, China
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\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
\r\n
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
\r\n
\r\n\t
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
\r\n
\r\n\t
\r\n
\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
\r\n
\r\n\t
\r\n
\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
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His research interests include optimization, computer graphics, computer vision, image processing, machine learning, pattern recognition, soft computing, data science, and intelligent systems. Prof. Sarfraz has been a keynote/invited speaker at various platforms around the globe. He has advised/supervised more than 110 students for their MSc and Ph.D. theses. He has published more than 400 publications as books, journal articles, and conference papers. He has authored and/or edited around seventy books. Prof. Sarfraz is a member of various professional societies. He is a chair and member of international advisory committees and organizing committees of numerous international conferences. He is also an editor and editor in chief for various international journals.",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"32650",title:"Prof.",name:"Lukas",middleName:"Willem",surname:"Snyman",slug:"lukas-snyman",fullName:"Lukas Snyman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/32650/images/4136_n.jpg",biography:"Lukas Willem Snyman received his basic education at primary and high schools in South Africa, Eastern Cape. He enrolled at today's Nelson Metropolitan University and graduated from this university with a BSc in Physics and Mathematics, B.Sc Honors in Physics, MSc in Semiconductor Physics, and a Ph.D. in Semiconductor Physics in 1987. After his studies, he chose an academic career and devoted his energy to the teaching of physics to first, second, and third-year students. After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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