\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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This resulted in the identification of novel platforms for the bio-transformation of industrial residues into valuable products, which represents a major advance toward sustainability. The overall goal of this book is to present and discuss the recent advances in metabolic engineering and bioprospecting of yeast for industrial applications in white biotechnology. Thus, this book will cover three different topics, including 1) Yeast bioprospecting for industrial biotechnology, 2) Metabolic engineering of yeast, and 3) Synthetic biology of yeast. The first topic will cover the identification of novel/unconventional yeast species and strains that can be used to produce valuable products (e.g., biofuels, flavours, and bioactive compounds). The second topic will discuss the current advances in metabolic engineering of yeast with the use of recombinant DNA technology. Finally, the third topic will summarise the current cutting-edge technologies that can be used to engineer yeast-based synthetic biofactories to produce valuable compounds and their social, economic, and environmental implications.
",isbn:"978-1-83768-320-8",printIsbn:"978-1-83768-319-2",pdfIsbn:"978-1-83768-321-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"59798f67726930812681288f1182340f",bookSignature:"Dr. Miguel Fernández-Niño",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12145.jpg",keywords:"Yeast Bioprospecting, Biofuels Production, Industrial Biotechnology, Bioactive Compounds, Recombinant DNA, Heterologous Expression, Genetic Engineering, Metabolic Engineering Gene, Genome Editing, Pathway Engineering, Systems Biology, Fine-Tuning Gene",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 3rd 2022",dateEndSecondStepPublish:"July 1st 2022",dateEndThirdStepPublish:"August 30th 2022",dateEndFourthStepPublish:"November 18th 2022",dateEndFifthStepPublish:"January 17th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Dr. Miguel Fernández-Niño is a biologist from The National University of Colombia with a master’s degree in Biochemistry from the same institution and a Ph.D. in Biochemical Engineering from Jacobs University, Bremen, Germany. He is currently working as a researcher at the Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany. He is recently awarded the Georg Forster Research Fellowship for postdoctoral researchers from the Alexander von Humboldt Foundation.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"158295",title:"Dr.",name:"Miguel",middleName:null,surname:"Fernández-Niño",slug:"miguel-fernandez-nino",fullName:"Miguel Fernández-Niño",profilePictureURL:"https://mts.intechopen.com/storage/users/158295/images/system/158295.png",biography:"Dr. Miguel Fernández-Niño is a biologist from The National University of Colombia with a master’s degree in Biochemistry from the same institution and a Ph.D. in Biochemical Engineering from Jacobs University, Bremen, Germany. He is currently working as a researcher at the Leibniz Institute of Plant Biochemistry, Halle (Saale), Germany. Dr. Fernández-Niño has extensive experience in synthetic biology, metabolic engineering, genome mining/editing, and molecular biotechnology, which can be applied to engineer and improve microorganisms with biotechnological applications.",institutionString:"Leibniz Institute of Plant Biochemistry",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Leibniz Institute of Plant Biochemistry",institutionURL:null,country:{name:"Germany"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"13",title:"Immunology and Microbiology",slug:"immunology-and-microbiology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"466997",firstName:"Patricia",lastName:"Kerep",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/466997/images/21565_n.jpg",email:"patricia@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully"}},relatedBooks:[{type:"book",id:"10741",title:"Synthetic Genomics",subtitle:"From BioBricks to Synthetic Genomes",isOpenForSubmission:!1,hash:"eb1cebd0b9c4e7e87427003ff7196f57",slug:"synthetic-genomics-from-biobricks-to-synthetic-genomes",bookSignature:"Miguel Fernández-Niño and Luis H. 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\nThe principles of active preservation and participatory management of historic cities that emerged after the Valletta meetings held by the Scientific Committee on Cities and Historic Villages (CIVVIH) of ICOMOS and adopted in the charter (ICOMOS) of November 2011, contain the fundamental guidelines on the development and active conservation of cities and historical areas. The objective is to guarantee the respect of the material and immaterial values of the urban cultural heritage starting from the knowledge of the places and the specificities of the single assets to promote enhancement and revitalization processes that allow their conscious re-entry into the incessant flow of the contemporary city.
\nIn the absence of clear planning and without a long-term systemic design any redevelopment project is destined to fail. In this sense, “valorisation is proposed as a necessary correlative of conservation, as a search for appropriate functions expressing the social need in an active involvement of the subjects in charge of protection” [3]. This involvement must take into account the specificities of the individual asset, promoting “the knowledge, the compatible use proposal, the intervention project” [3].
\nIt is within the design themes that a balanced relationship can be found between preservation and transformation of cities, territory for integrated and coherent interventions aimed at sustainability and regeneration, since each project of re-use and re-functionalisation to be effective it must necessarily be placed in a historical perspective.
\nFrom this point of view, the role of the historian or, to put it in the words of Henri-Irénée Marrou, of historical knowledge in the processes of valorisation of the urban, material and immaterial cultural heritage, becomes crucial because it contributes to “unravelling the tangle of stratifications, of meanings, of the design drawings of the past. From this clarification the city is made comprehensible, articulated, available also to non-destructive interventions at different scales. […] History is fundamental for understanding the existing city, for knowing things from the past but above all for being able to correctly read what still survives. Every theory—and therefore also a theory of reuse—must […] be based on the knowledge of the object before proposing interventions” [5].
\nThe necessary rethinking of the cultural heritage of historical centres and their conversion of values passes through the reactivation of the primary functions of the spaces of commerce, socialization, culture and art; a reconversion that cannot happen correctly without an adequate historical investigation that rediscovers and makes identity and vocations re-emerge, past functions and future potentials. It becomes imperative, in this framework, the need to start regenerative processes of systemic cultural innovation that reaffirm the identity of places and their collective memory through innovative models aimed at implementing new technologies and systems able to connect “territories, heritage and people in a logic of smart heritage” [6].
\nTo really be able to preserve and promote over time a value development of the asset and of the territory connected to it, the re-use project must intercept and generate new connections, reinvigorating the social fabric around it and stimulating participatory processes aimed at the implementation of innovative and flexible solutions, open and inclusive, able to face the multiple challenges of the globalized society. Managing the complexity of the present, to be understood as a resource rather than a constraint, means encouraging collaboration between transversal, multidisciplinary and cross-media skills, promoting contacts and contaminations to trigger interconnectivity and pluralism.
\nThe recent multiplication of urban laboratories and calls for ideas and projects aimed at creating places for innovation and social inclusion is an indication of the need, felt by many, to envisage development processes focused on the redevelopment of “hybrid spaces to cultural and creative vocation in which […] it is possible to work, produce, distribute, aggregate” [7]. The ability of those assets to acquire new values is a function of their availability to intercept and welcome active relational networks becoming “containers of planning that civil society is able to express through organized and stable actions” [7].
\nAlready in the Amsterdam Declaration of 1975 the “extensive” nature of conservation no longer confined to the sole protection of buildings of particular architectural and environmental value but aimed at safeguarding historic cities in the more general objective of “reshaping the contemporary city to improve the quality of life” by introducing the definition of active integrated conservation as a “joint action of restoration techniques and the search for appropriate functions.”
\nThe need to envisage interventions aimed, on the one hand, at the recovery of the asset subjected to safeguarding activities, from another, to its functional reuse, leads us to look at the problem of reuse from several points of view; the experiences of urban regeneration can represent in this sense “a genuine lever for the enhancement of the assets of the public heritage” [9] as well as opportunities for the development of cultural sites of degraded cities or left on the margins of redevelopment policies.
\nThe ever-increasing number of disused buildings that time and obsolescence have put into the register of works impossible to recover is such that they have led to tracing real geographies of abandonment where the numerous unused, abandoned or never really used buildings, scattered throughout the national territory, are carefully listed. Poised between memory and obsolescence, these buildings ask to be recovered by giving them back, at least in part, the function they had originally been called upon to satisfy. The intervention methodologies for the correct re-entry of these building complexes in the vital fabric of the cities go in the direction of returning to them a renewed function, as more flexible and homogeneous in terms of type and purpose, providing solutions open to future modifications and evolutions, the only viable way to start active safeguard policies of the historical-artistic heritage. In this perspective, forgotten historic buildings and places return to assume a strategic role within an urban ecosystem increasingly aimed at stimulating contamination between the various sectors of the economy and the urban social sphere and generating new connections.
\nStarting from the meaning of integrated conservation meant not as a “passive” defence, but as a dynamic protection activity “including the specific profiles of knowledge, restoration, use and enhancement of the same assets” [10] and against an idea of protection meant as a museum of architecture and the city, the building events that have affected the historical-artistic heritage over the centuries testify to the themes of functional and technological innovation, of the expansion and transformation of historical typologies as a necessary consequence of “adaptation” to the needs of society and as a first, “empirical,” response to conservation issues. But what reorganization of existing structures should we imagine in relation to their size, historical typology and location in the territory, also considering the experimentation of new techniques and the pressing demands of inclusiveness and overcoming of architectural barriers?
\nThe paper deals with the theme of the reuse of architectural heritage in Naples in reference to three buildings in the historic centre, different in type and original functions, but united by conversion projects under-way aimed at cultural and collective re-use: the seventeenth-century church of the Saints Cosma e Damiano, in the ancient heart of the city, part of the Great Project Historic Centre of Naples enhancement of the Unesco site; the Royal Hotel of the poor, from the mid-eighteenth century, used as the seat of the
In 1995 part of the historic centre of Naples was declared a UNESCO World Heritage Site. Its road layouts, the importance and richness of its historic buildings, its squares and its architecture, were recognized as universal values capable of projecting its own ray of influence
The opportunity offered by this important designation has made it possible to orient the planning of the areas of the historic centre towards initiatives aimed at safeguarding and protecting cultural heritage with particular attention to their enhancement in relation to the environment and active citizenship. The regeneration project of the historic centre, inserted in the broader context of the Integrated Urban Program of Naples, provides for systemic and participatory interventions able to promote the protection and enjoyment of the cultural resources of the historic centre and its ancient productive vocations by renewing the memory of the places in a contemporary key, enhancing the tourist offer and developing the establishment of a truly extended chain of cultural assets played around the themes of reception and inclusiveness. Through territorial policies aimed at encouraging public and private entrepreneurial initiatives, Naples, city of art and culture, is preparing to address the issue of a cultural economy based on production and on the value innovation of the tangible and intangible assets of its historic centre [11].
\nConsistent with what has been outlined so far, the Project for Naples identifies two privileged areas of intervention for the regeneration of the historic city consisting in the reuse of the abandoned building heritage and in the transformation of the common areas on the ground floor of the recovered buildings to be transformed into “poles of cultural and social animation (also through the inclusion of tertiary activities with a high artistic, cultural or social level) [14].” The aim is to start a redevelopment that, while aiming to protect and enhance the historical-artistic heritage, is not limited to “single-purpose” interventions but acts as a pivot of attractiveness and as a stimulus for the economic and social development of the territory [14].
\nThe introduction of new functions compatible with the nature of the buildings subjected to protection activities and the inclusion of re-creative, exhibition and educational activities on the ground floor of the recovered buildings aims at transferring an “urban value” within a private space belonging to the city. Between the street, the vestibule, the courtyard and the ground floor rooms, the urban system and the building system hybridize, merging into a relationship of reciprocal dynamic relationship to determine the extension of the axis of the road inside the courtyard of the building.
\nThe church of Santi Cosma e Damiano on the Largo dei Banchi Nuovi, rises in an area originally close to the Greek walls, in the stretch that delimited the ancient centre of the city towards the sea, in a western direction, along the axis of Via dei Banchi Nuovi has become over time one of the main directions of development of the coastal fabric enriched during the Middle Ages with the growth of villages and neighbourhoods linked to the economy of the Porto Piccolo. A commercial vocation confirmed and consolidated even in the Angevin and then modern times when the area became the privileged site of laboratories and merchant houses, welcoming a large number of lodges for commercial activities. Rua Catalana, Via Scalesia, Rua dei Fiorentini, Via Loggia di Genova, Via Loggia dei Pisani, are just some of the paths that still today meet near the port, testifying to the cosmopolitan and mercantile character of the places.
\nThe general layout of Piazza dei Banchi Nuovi dates back to the period between the sixteenth and seventeenth centuries. Due to riots in the city, in fact, around the middle of the sixteenth century the ancient Banco dei mercanti, located in piazza dell’Olmo, was destroyed; in the same period Alfonso Sánchez de Luna, marquis of Grottole, engaged in the construction of his own residence at Largo San Giovanni Maggiore, started the opening of the Largo dei Banchi Nuovi behind the building of which he would have marked the south-eastern margin. The opening of the square was the occasion to start the construction of the Loggia dei Banchi Nuovi on its southern edge, replacing the structures that had previously been destroyed; the construction of Palazzo Orsini, then of the Dukes of Casamassima, located on the south-eastern side of the square, whose renaissance forms—still legible—were transformed by Ferdinando Sanfelice in the eighteenth century. The completion of the Largo occurred during the first half of the seventeenth century with the construction, on the northern side, of Palazzo Vernazza (or Vernasse), transformed into Sanfelice’s forms in the first decades of the following century.
\nThe “vertical” connections between the Largo dei Banchi Nuovi and the lower city were ensured by a network of paths and lanes that still today branch off into the valley, filling the gap between the ancient city centre and the orthogonal plant checker-board, and the maze of alleys and lanes that cross the area near the harbour. The Banchi Nuovi square is in this sense the junction or, even better, the welding point between the centre of Neapolis and the lower city, marked by the convergence of the Via di S. Chiara and by the rise, starting from the early modern age along the extension of its upper limit, of a series of noteworthy buildings: from the renaissance complex of Santa Maria la Nova (fifteenth to sixteenth century), to the church of Santa Maria dell’Aiuto (seventeenth century), from the Penne palace (fifteenth century), to the new church of Santi Demetrio e Bonifacio (early eighteenth century).
\nAt the beginning of the seventeenth century, with the abolition of the new lodge decreed for reasons of public order, the area underwent further transformations. The building of the Banchi Nuovi was first purchased by Sánchez and then resold, in 1616, to the Barbieri Congregation which transformed it into a chapel for its own congregation to replace the ancient seat along the Via dei Tribunali, which was sold to allow the construction of the complex of the Gerolamini. In October 1617 the new church was finished in its general form, although work continued inside it.
\nThe church, dedicated to the Saints Cosmas and Damian, fits into the square-shaped structure of the sixteenth-century Loggia composed of nine square spans covered by cross vaults supported by 16 trachyte pillars. The planimetric solution (Figure 1) adopted is that of a latin cross-shaped with a single nave, corresponding to the first two central spans of the Loggia, completed by two chapels on each side obtained by inserting walls in about half of the original side bays of the existing structure and ended by a high transept coinciding with the three terminal spans of the sixteenth-century Loggia [15]. “The interruption of the spatial continuity of the cross vaults” visible in the lateral rooms “was cleverly disguised […] by means of pseudo-arched arches supported by sails” [16]; next to the main body of the church, in the “residual” spaces of the Loggia, the sacristy was obtained, on the left hand, and the room intended for the congregation on the opposite side.
\nNaples, church of Saints Cosmas and Damian on the largo Dei Banchi Nuovi, ground floor plan [
Both on the main façade and on the lateral side of the church, along the Calata of Santi Cosma e Damiano, the triple round arches on trachyte pillars that conformed the once-open arcades of the Loggia dei Banchi Nuovi are still visible. The main façade of the church, concluded at the top by the cornice and the small bell tower surmounted by the cross, presents, above the seventeenth-century trachyte portal, a large late-Baroque window decorated with rocaille stuccoes (Figure 2). On the other hand, the oval openings in façade facing the upper rooms that flank the nave, date back to nineteenth century.
\nNaples, church of Saints Cosmas and Damian, relief drawing of the main and lateral façade [
The church, abandoned since the eighties of the twentieth century and subject to continuous theft and vandalism, is the object of the interventions of recovery and functional enhancement conducted by the Municipality also because of the crucial role played by Largo dei Barchi Nuovi compared to the surrounding territory (Figure 3). Precious open space in a maze of streets and buildings mainly for residential use, it is in fact a strategic gathering and meeting place for young people, as well as being used for multiple vocations.
\nNaples, church of Saints Cosmas and Damian and the largo Dei Banchi Nuovi.
Specifically, the intervention in progress concerns the redevelopment and re-functionalisation of the church of Saints Cosma and Damiano, whose re-use is aimed at creating multi-purpose and flexible spaces to be used for cultural activities, with particular reference to exhibition purposes, music, conferences and training. The building, in fact, rises in the centre of a nucleus that condenses strong identity values around itself: from the music pole, which has a privileged reference point in the nearby Conservatory of San Pietro a Majella and in the adjacent street of musical instruments; at the pole of culture and knowledge constituted by L’Orientale University of Napoles, from the twentieth century owner of the ancient Sánchez palace, and from the Federico II University, whose headquarters is located along the Via di Mezzocannone on which the extension of Via dei Banchi Nuovi converges.
\nThe presence of important tourist flows due to the proximity to the art itineraries of the ancient centre has determined the demand for spaces and services for culture, leisure and hospitality. The current project includes, among its main objectives, the enhancement of the local artistic and artisan fabric; improving services to citizens with the consequent increase in safety and legality; the promotion of initiatives aimed at rediscovering craft and creative vocations through an integrated approach that affects the environmental, social and economic degradation of the neighbourhood by activating participatory processes of systemic cultural enhancement and development and modernization policies.
\nThe Sangro di Fondi palace rises on the eastern side of Via Medina in an area characterized by imposing architectural works dating back to the Angevin and Aragonese periods when, the identification of Castel Nuovo as the residence and political and administrative centre of the city, determined the coagulation of houses and aristocratic residences linked to the presence of the palace. The original structure of the palace can be traced back to the first half of the sixteenth century when Michele Giovanni Gomez, president of the Royal Chamber of the Sommaria, bought a series of neighbouring houses to build his own family palace [17]. Beginning in the seventeenth century, the first changes were registered in the planimetric distribution of the building, organized around a main rectangular block along the Via Medina and with three other smaller volumes behind which the rectangular courtyard will take shape. The main body of the nucleus along Via Medina has a base plan marked by a trabeated portal that leads into the large internal vaulted atrium, and from the entablature on which the windows of the noble floor are set, followed by the mezzanine floor concluded at the top by the cornice and the double-pitched roof. In 1698 the palace was sold by Gomez to the Marquis of Genzano, Stefano de Marinis, who entrusted the transformation work to Giovan Battista Manni, active in the construction site in the years between 1704 and 1714. The intervention carried out mainly concerned the construction of the portico on the counter-façade with the arrangement of the large courtyard and the apartments on the noble floor. In 1709 the monumental staircase to the right of the entrance hall was redone and the following year the serliana (Figure 4) was built on the bottom of the courtyard—concluded by a terrace delimited by a loggia composed of three arches at full centre on columns with trachyte bases—which symmetrically incorporates the analogous solution present in the counter-façade (Figure 5). In 1712 the entrance portal was modified, enriching it with two powerful marble columns and the overlying central balcony, corresponding to the ballroom on the main floor, decorated with frescoes by Giacomo del Po’. The first arrangement of the main facade dates back to this period, with the regularization of the openings and the realization of the elegant facade stuccoes documented in the engraving by Carlo Petrini of 1718. Between 1720 and 1760 the works continued under the direction of Gaetano Di Tommaso who completed the decorations on the first floor, transforming the party room and the private chapel. The very presence of the engineer Di Tommaso, a collaborator of Luigi Vanvitelli in the works of Palazzo Berio on Via Toledo and in the properties of the Casacalenda family, led to the attribution of the building—not supported by documents—to Vanvitelli, as reported by Francesco Milizia and as reported also by Chiarini in his edition of Celano, where we read: “the building […] belonged to the old Marquis of Genzano, but afterwards by hereditary right […] it passed into the domain of the Prince of Fondi. The building was built after the middle of the last century with a drawing by Cav. Luigi Vanvitelli. The door is all in marble, decorated with two columns of Ionic order, and the windows of the noble floor are formed in tabernacles with pillars of the same order. The details do not have the merit of the others operated by the distinguished architect; but the set of architectural lines is grandiose, the distribution of the space is regular, the appearance is imposing. The discovered court is beautifully decorated; and a superimposition of delightful terraces very elegantly designed, adds to it beauty and nobility. The scale treated in the upper landings is also of great value with the convenience and grandeur that Vanvitelli was able to find in all his works” [18].
\nNaples, Fondi palace on Via Medina, ground floor plan. Available from:
Naples, Fondi palace on Via Medina, inner courtyard and particular of the Serliana (photo of the author).
From the mid-eighteenth century there were further transformations and growths due to the purchase of adjacent real estate units until, in 1798, the main façade was rebuilt, with the complete elimination of the stucco decorations documented by Petrini, and the elevation of a second noble floor (Figure 6).
\nNaples, Fondi palace on Via Medina, detail of the other Serliana on the counter-façade in the courtyard (photo of the author).
The configuration reached at the end of the nineteenth century does not present significant transformations until the early twentieth century when the building, which became the seat of the Fascist provincial federation and Casa del Fascio, underwent massive transformations that changed its appearance. The transformation of the roof into the terrace dates back to this period—it was accessed from a new floor created above the second noble floor and set back from it—and the addition of a central turret eliminated after the second World War when the building was the seat of the Communist Federation.
\nThe redevelopment project started in 2014 by the State Property Agency, owner of the property, and coordinated and developed by Ninetynine Urban Value with the collaboration of the Municipality of Naples and various institutions such as the Federico II University and the Fine Arts Academy of Naples, aims to restore a historic building to the city for some time unused through a diversified and temporary conversion program of the building that favours its enhancement also in terms of knowledge and functional innovation, minimizing the risks deriving from its prolonged inactivity and encouraging the availability of creative incubators to be allocated to students and young entrepreneurs. The building—with a total surface area of 4432 square meters—hosts multi-functional spaces for art, culture, experimentation, events, places of comparison and coagulation, itinerant exhibitions and conferences open to the city and the network of public and private stakeholders interested in collaborating with institutions to initiate participatory processes for the enhancement and integrated use of the tangible and intangible cultural assets of the historic city (Figure 7). The objective is to create a contemporary place where art, culture, experimentation and multidisciplinarity can give rise to new initiatives, promoting collaboration and contact between companies, the world of education and culture, institutions and civil society [19].
\nNaples, facade of the palace de Marinis di Sangro, then Fondi, engraving by P. Petrini, 1718 (National Library of Naples).
It was to fulfil social stability problems that Charles III of Bourbon commissioned Ferdinand Fuga in 1749—returning from the Roman shipyards of San Michele in Ripa Grande and the extension of the Santo Spirito in Sassia Hospital (1742–44)—to build in Naples the largest Hospice in Europe, capable of accommodating eight thousand marginalized, providing them with adequate living and working conditions [20]. “It was destined for eight thousand poor, to be divided into four classes, that is, of men, women, boys, and girls, without any communication between them. Annexed to the aforementioned Hospice he designed a vast public church, to be visited separately by the four aforementioned classes. There were great conveniences such as laboratories, refectories, courtyards, arcades, workshops, and servants’ and executives’ quarters” [21].
\nCharacterizing sign of such institutes it was precisely to place oneself as a poles of development and social cohesion with respect to the territory, creating the conditions so that artisan activities and trades could arise around them able to revive the urban economy in crisis, determining opportunities for work and development for an ever increasing number of inhabitants.
\nThe theme of assistance to the poor was certainly not new in the mid-seventeenth century and was part of that program of raising awareness of the social recovery of entire groups of needy and abandoned people who, from France to the rest of Europe, would have spread rapidly, identifying in the Hospices and in the Internment Houses the solutions adopted to limit and correct the damages deriving from begging and poverty. Precisely the number of such institutions can be considered an effective parameter of evaluation to understand the importance assumed by a city centre compared to the others: the more they were productive and economically independent, the greater was the number of welfare structures built within them to stem the security and social problems. The awareness of the need to identify in the work a more effective rehabilitation function than mere isolation, led to the “ethical condemnation of idleness” [22]. It was no longer a question of “locking up the unemployed, but of giving work to those who had been locked up, making them participants in common prosperity” [22]. The significance of this operation was more economic than ethical and consisted in supplying low-cost labour during periods of full operation, and in forming and keeping prisoners engaged in times of crisis [22].
\nPrecisely “the capacity of such structures […] to adapt to the rapidly changing new socio-economic scenarios will mark their destiny: the decline, when their function will be reduced to an amorphous commitment to care, or an active role, when they succeed in integrate into the industrial processes already in place since the second half of the eighteenth century, and recover a more articulated relationship with civil society outside the walls” [23]. The idea of making the Hotel of the poor a town-building, conceived as a self-sufficient community body, reflected on the very nature of the proposed projects. Whether you look at the first project, based on a square plant internally divided into four courts, to be erected in the village of Loreto, in the eastern area of Naples; whether the definitive project is observed, organized on the succession of five majestic courtyards-squares, to be built in the village of Sant’ Antonio Abate, in a crucial area for connections with Rome and city traffic, one cannot but consider the importance that the new factory was called to cover the intentions of the sovereign. Located at the foot of the Capodimonte hill, along the extension of the avenue that led to the sumptuous villa of Poggioreale (Figure 8) [24], one of the most elegant and celebrated dwellings of the early Neapolitan renaissance, the building, of which only the three central courtyards were built, competed for dimensions (600 m/140) and architectural language with the royal residence of Caserta, the last “anachronistic” example of capital-city of monarchical absolutism (Figure 9).
\nScenic view to the west of the city of Naples in the Campagna Felice, detail of the map of the Duke of Noja, Naples 1775 with in evidence of the Hotel of the poor (Albergo Dei Poveri) in the original project articulated around five courtyards [
Late eighteenth-century engraving depicting the two large factories built by Ferdinando Fuga in Naples in the second half of the eighteenth century: The Hotel of the poor in the project actually built with only three central courtyards; and the massive block of the granary factory [
The construction of the Hospice for the poor unfolds over a period of time ranging from the death of Ferdinando Fuga (1782), to Mario Gioffredo, to the intervention of Carlo Vanvitelli (1785–1799) and from these to Francesco Maresca (1802), author of the definitive reorganization of the Fuga’s project.
\nThe architectural language adopted by the florentine architect suggests a double interpretative key: on one side the late baroque vein, which can be found in the unfinished Panoptikon church located in the middle of the intermediate courtyard; from another the classicist vein with which the development of the whole building is solved, like the Granili (550 m) played on the poetics of the large dimension and on the landscape scale of the intervention. The plan of the church, in the first solution envisaged for the village of Loreto, presented a series of internal open galleries on the aisles according to an organization experimented by Fontana in the church of San Michele a Ripa, from which the subdivision by classes of the interior spaces was taken. In the transition to the final site, the church’s design is also considerably complicated with the position of the dome that has been moved back compared to the more soaring and looming initial solution.
\nThe dimensions of the building, as partially realized, have a width of façade equal to 360 m length for 140 m of width; with an area of 100,000 m2 and a volume of 830,000 m3.
\nWith its 430 rooms and 20,000 m2 of outdoor spaces, the colossal structure, far more imposing than the Roman factory, has always been considered a “false step” in the Bourbon government policies. “Who knows when it will end? And it is almost thirty years that this work is being done. With less expense, and in a shorter time, it would have removed all poverty from the abundant Kingdom of Naples. But this is not the business of the architect, but of good government” [25].
\nYet, seen from the ring road, the Hospice for the poor clearly conveys the meaning of its construction. The proportion it establishes with the metropolis that grew up around it tells with unparalleled efficacy the significance of the strategic operation conducted at the time by the Bourbons: it was a city in the city that was intended to be built, the “city of services,” placed at the entrance to the capital of the kingdom (Figure 10). More than the constructive aspects of the Hospice for the poor, it is interesting to underline the propelling role that it was called to play over the surrounding territory when, in the wake of the industrial revolution and the new modes of production, it became an “incubator” of companies and trades .
\nNaples, aerial view of the Hotel of the poor.
Already Ferdinand IV of Bourbon had created the premises so that an industrialization process would be started up within it, aimed at identifying in the two poles of vocational training and education the cornerstones around which to rotate, for productive purposes, the functional reuse of the building. The advent of the French and the return of the Bourbons marked the years of greater productivity and “flexibility of use” of the Hospice for the poor. The building became the centre of a strategy aimed “at constituting an effective place of intersection between the programmatic function of public interest and […] the executive role of private individuals” [26]. Not only was it the site of various production activities, but it became a production centre connected to other important institutions located throughout the territory thanks to a series of contracts and activities that regulated the relationships: a sort of clusters that worked in synergy with the head office. This is the case of the coral factory, started in Torre del Greco but established with its own independent workshop also in the Hospice for the poor, or of the nautical school which, started by the marquis Tanucci, saw its flowering in 1816 thanks to its collaboration with the youth of the hotel.
\nOn the other hand it was during the Bourbon period that the idea of establishing a “widespread cultural chain” in the kingdom of Naples was affirming itself. From publishing, to local production systems, from silk factories to laboratories in the Hospice for the poor, a fine-tuning of a formidable production system spread over the territory, which identified the levers for future development and growth, is outlined. The silk factories of San Luecio, the farm of Carditello, the corals and ceramics factories, the tapestry makers, the factories for the production and spinning of wool, the printing press, the metal laboratories are another way to read in watermark the history of Neapolitan architectural culture at the turn of the nineteenth century, within which a fundamental role was played precisely by the Hospice for the poor, a true breeding ground for arts and crafts, a production center embedded in the ancient heart of the city.
\nThe theme, nowadays very current, of the cultural industry as an element capable of introducing, in the wider economic system, a market of beauty and culture was started already by the Bourbons not only as an instrumentum regni, but as a project capable of triggering productive processes able to feed innovation, research and creativity within a “knowledge pole” supported by the policies of the kingdom. The rediscovery of Pompeii and Herculaneum and the resulting archaeological excavation campaign, with the consequent relief, design and publication of the exhibited antiquities of Herculaneum, gave rise to studies and research in the most diverse fields of knowledge and artistic production, donating new life and inspiration to painters, sculptors, academies and to the textile sector itself whose reproduction of fabrics, prints and decorative motifs was inspired by that formidable repertoire of cultural forms and traditions that emerged from the excavations, giving impetus to the economy and to artisan production.
\nCalled the Grand Emporium of the most varied Arts and Manufactures, the Hospice for the poor played an important role in the economic and commercial development of the capital. In the mid-nineteenth century, “it swarmed with activity: […] from the large […] spaces destined to the remittances for the train of the Royal artillery, to the spaces for […] the foundry, the engraving, […] the glass-works, […] the dyeing of wools, […] the hall of mergers, […], the school of Fine Arts” [27], showing its multi-functional nature, a consequence of the modular structure of the building.
\nAfter various vicissitudes and various restorations, the last of which is still in progress, the Municipality of Naples—which acquired since 1981 the building in its own patrimony—has since 1999 prepared the “Real Hospice for the poor Recovery Project” coming to identify in the
The rationalization of internal routes, consisting of nine kilo-meters of corridors; the clear distribution of the environments; the articulation of the buildings around the three large courts; the “serial” repetition of the facade modules, allow a functional restructuring of the building that respects the construction characteristics, keeping the type unaltered.
\nPrison, laboratory, factory, school, the Hospice for the poor can guarantee a flexible and plural use of its interior spaces, combining some of the great themes around which revolves public buildings to be used as spaces for the community and taking into account of a new, “ancient” social emergency that the chronicles of our days dramatically tell: that of acceptance and inclusiveness.
\nThe projects of reuse and conversion of the three analysed Neapolitan buildings, characterized by different types, will allow to preserve their historical memory by activating regenerative urban processes aimed at the promotion and development of activities and services for the community. These interventions present aspects that may lead us to consider them as possible reference models in terms of reusing historic buildings that have been restored over time to their renewed collective function, able to actively promote the development of the surrounding urban area in a logic of smart heritage.
\nThis chapter is dedicated to selected methods used to analyse the biocompatibility/cytotoxicity of different nanomaterials. The effect of nanomaterials on cellular metabolism and relative viability can differ according to their properties and experimental design. As shown by Frewin et al. [1], biocompatibility analyses of novel materials for medical applications are conducted using quantitative and qualitative techniques. These techniques have been collected by the International Standards Organization (ISO) 10,9931 (ISO-10993-1, 2009; ISO-10993-5, 2009; ISO-10993-6, 2007).
Nanotechnology and nanobiotechnology have focused scientists’ attention in the last few years on their application in biomedical research, such as detecting and monitoring systems of cells within the body, delivery systems for various drugs, hyperthermia treatment, photodynamic therapy and tissue engineering [2]. The term ‘nano’ may be considered a different state of aggregation of matter in all its states—solid, liquid, gas and plasma [3].
The phenomenon of nanoparticles is based on their different physical (optical and electromagnetic), chemical (catalytic) and mechanical properties that depend on particle size, as well as surface and quantum effects. The surface effects manifest as scaling of physical properties (increased atomic fraction on particle surface compared to the interior), which includes increased chemical reactivity and reduced melting point of nanoparticles compared to larger particles of bulk material. NPs have a very large surface area in comparison to microparticles and larger materials, making this large surface area available for chemical reactions [4]. In addition, nanoparticles can be classified according to their composition (inorganic and organic, lipid-based and polymeric NPs), dimensionality, morphology, uniformity and agglomeration [Table 1] [3, 5]. Another classification divides nanomaterials into three groups: zero-dimensional materials (quantum dots), varying in shape and diameter; one-dimensional materials (nanorods and nanowires) and two-dimensional materials (nanobelts, nanodisks and nanosheets) [2].
Classes | Types | Structure | Size | Properties |
---|---|---|---|---|
Carbon-based nanoparticles | Carbon nanotubes (CNTs) | Single-walled CNT (SWCNTs) Multi-walled CNT (MWCNTs) | Diameter between 0.4 and 100 nm; length between several nanometres up to centimetres | Improved compressive strength, tensile bending strength, flexural strength, durability, piezoelectric response, sensing ability |
Graphene (GF) and graphene oxide (GO) | Hydrophobic two-dimensional single monoatomic layers (GF) Oxidised form of GF (GO) | From 0.1 up to 300 μm | Large area; its surface can be easily functionalized with functional groups; ideal for high drug loading via π-π stacking, hydrophobic or electrostatic interactions; exceptional mechanical properties | |
Nanodiamonds (ND) | Truncated octahedral structure | Diameter between 2 and 10 nm | Large area, enhanced biocompatibility, good mechanical strength, surface functionality, colloidal stability | |
Inorganic nanoparticles | Gold nanoparticles (GNPs, AuNPs) | Colloidal gold, nanorods, nanowires | Sizes of 1–100 nm | Absorb and scatter light; catalyst applications; anti-fungal, anti-microbial properties |
Silver nanoparticles (AgNPs) | Colloidal silver, spherical silver nanoparticles, diamond, octagonal, thin sheets | Diameter between 1 and 100 nm in size | Significant anti-microbial properties | |
Iron oxide nanoparticles (IONPs) | Magnetite (Fe3O4); oxidised form maghemite (γ-Fe2O3) | Sizes of 1 and 100 nm | Superparamagnetic properties; the surface area-to-volume ratio is significantly high; higher binding capacity and excellent dispersibility | |
Mesoporous nanoparticles (MSN, MSNPs) | Nanosilica | Solid material with a porous, hexagonal, cubic and cage type | 50–300 nm | Porous structure and large surface area; chemical stability; surface functionality and biocompatibility |
The toxicity and cytotoxicity of nanomaterials are complex and depend on various factors, such as chemical composition, crystalline structure, size (at the nanolevel, the basic physicochemical properties of materials can change with variation in size) or aggregation. Nanomaterial composition determines its chemical interaction with cells, cellular uptake mechanisms and intracellular localisation. Chemical composition may also induce oxidative stress. For example, silver nanoparticle aggregates are more toxic than asbestos; CNTs are highly toxic and evoke much more damaging effect to the lungs than carbon black or silica NPs, but titanium oxide, iron oxide and zirconium oxide NPs are less toxic than asbestos [3, 6].
The crystalline structure effect of NP toxicity causes that some nanomaterials with a specific crystalline structure do not exhibit high toxicity, but other allotropes can strongly affect cell viability and exert an effect on human organism. Sato and co-workers [7] demonstrated that TiO2 allotropes exhibited different toxicity. Rutile TiO2 NPs (200 nm) induced oxidative DNA damage in the absence of UV light and also TiO2 NPs (10–20 nm) stimulated reactive oxygen species (ROS) production under corresponding conditions; in contrast, anatase NPs of the same size did not cause this effect [3, 8, 9].
Another factor that determines nanomaterial toxicity is the size of NPs. In most cases, smaller nanoparticles are able to pass through physiological barriers. Small-size nanoparticles can enter cells by phagocytosis and other mechanisms (e.g., micropinocytosis, receptor-mediated endocytosis (RME) pathways mediated by caveolae, clathrin and caveolae/clathrin-independent endocytosis) [10, 11]. NP ability to enter the cells determines adhesive interactions, such as van der Waals forces, steric interactions or electrostatic charges [3, 12, 13]. Moreover, NPs smaller than 100 nm are not phagocytized as opposed to larger nanoparticles, but they enter via RME pathways [2, 11]. NP uptake can also occur in the absence of specific cell surface receptors. Nanoparticles smaller than 50 nm can easily enter most cells (with greater cytotoxicity), while nanoscale devices smaller than 20 nm can cross blood vessels and cumulate in tissues [2]. Particles with larger surface area display tendency to agglomerate in the liquid, interact with molecules, such as proteins and DNA and may cause oxidation and DNA damage [3, 4, 14].
It is known that the shape (aspect ratio) also determines cellular uptake efficiency and may affect cell viability. Additionally, surface chemistry of nanomaterials modulates the response of biological systems and distribution in the organism. Surface functionalisation (with Fe3O4, gold nanoparticles; type of bonding on the surface, e.g., covalent, noncovalent; dispersing agents, e.g., PEG) is a crucial factor that can significantly change the toxicity of NPs and prevent NPs from aggregating; it can also change their fate in biological systems [2, 3, 11]. For example, functionalization of MWCNTs with sodium sulfonic acid salt (─SO3Na or -phenyl-SO3Na) increased their biocompatibility in comparison with unfunctionalised or carboxylic acid–functionalized (─COOH) MWCNTs [15]. Cellular uptake depends on different factors, such as nanomaterial and cell type, but also on environmental properties and the complexity of culture media. These specific conditions determine the aggregation process, which makes the interpretation of data on nanoparticle biodistribution or uptake difficult [3]. NP agglomerates affect and limit the direct extrapolation of
Intercellular localization of NPs and their interaction with cell components, such as the membrane, mitochondria, lysosomes and/or nucleus, are essential [11]. NPs can affect cell and organelle membranes, induce oxidative stress (ROS), DNA damage and mutagenesis and evoke apoptosis and protein up-/downregulation [11]; they can also modulate immune response [3, 17].
The cytotoxicity study is an essential and crucial step in testing novel substances/nanomaterials in the context of biological and medical applications. Assays based on tetrazolium salts, like MTT (2-(4,5-dimethyl-2-thiazolyl)-3,5-diphenyl-2H-tetrazolium bromide), nitroblue tetrazolium (NBT) and the second-generation tetrazolium salts, such as XTT (sodium 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)-carbonyl]-2H-tetrazolium inner salt), MTS (5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-2-thiazolyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt) and WST-1 (sodium 5-(2,4-disulfophenyl)-2-(4-iodophenyl)-3-(4-nitrophenyl)-2H-tetrazolium inner salt) are basic tools for cytotoxicity determination, but nanomaterial testing is associated with certain challenges. The type of nanomaterials, manufacturing conditions, colloidal dispersion, chemical purity and photocatalytic activity of NPs may determine the usage of most traditional assays. Interactions between nanoparticles and molecules (i.e., reactants) used in well-established assays significantly affect the results and are one of the reasons of result variations [18, 19]. In assays based on colorimetric and fluorescence measurements, it has been found that nanomaterials, such as carbon nanotubes (CNTs), graphene/graphene oxide nanosheets, TiO2 nanoparticles or boron nitride, interact with chromophore molecules, which may lead to false-positive results [19, 20, 21]. In other cases, the total surface area of NPs was sufficient to adsorb the reagent or fluorescent molecules, especially those with aromatic rings, which in turn led to false-negative results [21]. These results suggest using alternative cytotoxicity assays based on tetrazolium salts, e.g., XTT, WST-1, INT or other assays that complement the analysis, e.g., Alamar Blue (AB), neutral red uptake (NRU) assay, LDH leakage assay, flow cytometry, cell death analysis (using trypan blue or annexin V/propidium iodide), protein concentration measurements using the Bradford assay, measurements of mitochondrial membrane permeability (MMP) or loss of glutathione (e.g., GSH) and the activation of proinflammatory cytokines (e.g., IL-6, IL-8 and/or TNF-α) [15, 19, 21].
A number of studies have been carried out to verify the effect of NPs on assay reagents [22]. Wörle-Knirsch and co-workers [23] indicated that CNT analysed using the MTT assay caused false-positive results due to the strong interaction between CNT and the insoluble formazan crystals [19, 23]. In the aforementioned study, SWCNTs were analysed on A549 (human alveolar epithelial cell line), ECV304 (endothelial cells derived from umbilical cord) and NR8383 (rat alveolar macrophage cell line) cell cultures and the results obtained in the MTT assay were verified by WST-1, LDH, mitochondrial membrane potential (MMP) and annexin V/PI analysis. The MTT assay indicated that SWCNTs affected cell viability, reducing it almost by 60% after a 24-h incubation period. Moreover, the decreased cell viability did not recover after longer incubation or higher concentrations of nanotubes. The results of the MTT assay were verified using WST-1, and no reduction in viability was detected. LDH and MMP assays confirmed WST-1 results, and flow cytometry using annexin V/propidium iodide showed lack of necrosis and/or apoptosis. Wörle-Knirsch et al. [23] concluded that nanotoxicological assays needed standardising with regard to the tested nanomaterial
Lupu and Popescu [24] used the MTT assay to evaluate TiO2 toxicity. The effect of TiO2 nanoparticles on living models is crucial due to their utilisation in food, beauty care and pharmacology industries. Additionally, TiO2 nanoparticles are known to exhibit photocatalytic properties: the ability to catalyse redox reactions of molecules adsorbed on the surface during light exposition (λ < 385 nm). Photocatalytic reaction may occur by direct charge transfer of electrons (e−) and holes (h+) generated by light on the surface of titania nanoparticles. The reaction may be also mediated by reactive oxygen species (ROS), e.g., hydroxyl radicals (˙OH) or superoxide anions (˙O2−) formed at the interface of TiO2 and water. Lupu and Popescu [24] clearly demonstrated that TiO2 nanoparticles induced transformation of noncellular MTT to formazan. Formazan formation was found to be proportional to titania NPs, and this process was enhanced by daylight exposure. Moreover, the results obtained in the experiment without cellular model were validated using three cell lines—V79-4, HeLa and B16. The results demonstrated false viability that increased up to 14% for TiO2 concentrations higher than 50 μgml−1 [24]. In addition, the TiO2-MTT reaction was analysed in PBS environment. The reaction rate (formazan production rate) was proportional to TiO2 and UV radiations (at 312 and 365 nm wavelengths) and inversely proportional to initial concentration of MTT. Moreover, reaction efficiency was enhanced by the presence of Na2HPO4 (phosphate concentration of 0.005 M for maximum efficiency), which is the basic component of PBS [25].
Casey et al. [26, 27] proved that single-walled carbon nanotubes (HiPco®) interacted with indicator dyes applied in Coomassie Blue, AlamarBlue™, neutral red uptake, MTT and WST-1 assays. In all cases, nanotubes interacted with dyes, which resulted in the reduction of the associated absorption/fluorescent emission. A spectroscopic study demonstrated that SWCNTs interacted with Coomassie and reduced the absorbance for all concentrations tested (0.003–0.800 mgml−1). As regards the AlamarBlue™ analysis (fluorescent measurements of all single-walled carbon nanotube solutions), quenching was monitored as a function of SWCNT concentration and plotted as an emission ratio at 595 nm by 540 nm excitation for the AB assay (5% solution of AB in culture medium) against SWCNT concentration. Another assay measuring NR uptake also showed SWCNT’s ability to quench NR emission and was described as a function of SWCNT concentration. The MTT assay used in the cited study was found to interact with CNT. The reduction in MTT was associated with SWCNT concentration (absorption reduction was higher with increasing SWCNT concentration). For the WST-1 assay, it was concluded that the reduction in WST-1 absorbance was dependent on nanotube concentrations above 0.0125 mgml−1. Casey et al. concluded that Coomassie, AB, NRU, MTT and WST-1 assays were not appropriate for the cytotoxicity analysis of carbon nanotubes [26, 27].
Limitations of MTT in cytotoxicity studies on graphene and graphene-related materials have been demonstrated in numerous publications. CCK-8 (tetrazolium-8-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] monosodium salt) assays are an attractive alternative for the MTT test. Evaluation of graphene adsorption was based on cell-free adsorptive experiments and demonstrated a gradual reduction of MTT to 93% during 2-h incubation, whereas CCK-8 was significantly reduced to 73% after exposure to graphene for 2 h. The intensity of graphene adsorption to MTT and CCK-8 was time-dependent. The quantity of the CCK-8 reagent absorbed by graphene was higher than that of MTT. It was reported that the π-π conjugated system of the CCK-8 molecule was much stronger than that of MTT due to three benzene rings and one five-membered heterocycle. MTT contains only two benzene rings and two five-membered heterocycles. Another reason for that process is that benzene ring groups strongly affect the adsorption. It was also noted that graphene can suppress the fluorescence effect caused by electron transfer from the dye molecule to the graphene surface. Although MTT and CCK-8 reagents are not fluorescent dyes, both of them display a positive electron on the molecules, similar to some known fluorescent dyes. Thus, it is possible that electron transfer occurs during the incubation with graphene and interferes with the dye molecule that contacts the enzymes. Jiao et al. noted that CCK-8 molecules can be more significantly disturbed by graphene than by the MTT reagent. Additionally, optical properties of graphene may also result in the loss of light signals used for detection in assays
Cytotoxicity can also be determined using the lactate dehydrogenase (LDH) assay. The LDH assay is performed to exclude interactions between nanomaterials and fluorophore molecules [19]. The LDH assay, similar to the MTT assay, is a colorimetric method; thus, it can also interact with nanoparticles (e.g., CNT). Formazan crystals can be absorbed on the surface of MWNT (multi-walled nanotubes) through a strong π-π stacking interaction. The analysis of Ali-Boucetta et al. [19] proved that media containing the released LDH showed the same absorbance (at 490 nm) as MWNT:F127 (multi-walled nanotubes dispersed in the presence of Pluronic 127) dispersion in culture media. Ali-Boucetta et al. [19] proposed LDH assay modification that would eliminate the potential risk of interference of assay components with NPs (modified method vs. traditional procedure is presented in Figure 1).
Schematic of the original (A) and modified LDH assay (B) [
In the experiment of Han et al. [29], copper (Cu-40), silver (Ag-35 and Ag-40) and titanium dioxide (TiO2-25) were used to validate the popular assay. It was found that LDH was inactivated in the presence of Cu-40 and AG-35 in a dose-dependent manner. The effect of TiO2-25 and Ag-40 NPs was not significant. In conclusion, these authors underlined the necessity to interpret the results with caution because of metal-catalysed oxidation [29].
Wang et al. [30] proposed modifying the LDH assay that would correct the erroneous results caused by potential interference of nanotubes with reporter chromophore, resulting in its adsorption on nanoparticle surface. The idea of this modification is based on the incubation of LDH derived from a known number of cells (e.g., DH82 macrophage cells) or a purified LDH standard (lactic dehydrogenase enzyme purified from rabbit muscle) with a precise amount (at different concentrations ranging from 5 to 100 μgml−1) of SWCNT or SWCNT-ox (carbon nanohorns). This additional procedure enables the quantification of the effects of NPs on the LDH level. The results obtained by Wang and co-workers clearly demonstrated that LDH concentrations decreased with increasing CNT concentration (at a wavelength of 490 nm). On the other hand, the 580 nm peak was elevated at the increased maximum absorbing wavelength. Based on the observation and regression analyses performed by Wang et al. [30], it was suggested that LDH assay results should be verified by calibration curves in the presence of different SWCNT concentrations (in the range of 5–100 μgml−1) at two wavelengths, 580 and 490 nm, for each LDH assay. This procedure more accurately determines cellular toxicity values [30].
Smith et al. [31] presented a simple protocol modification of the LDH analysis, which included membered additional conditional-specific controls. This modification enables accurate simultaneous measurement of the effects of death and growth inhibition. The additional step provides quantitative information that can be useful in applications such as drug discoveries [31]. Another approach in LDH assay analysis was proposed in the experiments of Chan et al. [32]. Modification of the LDH protocol allows to detect necrosis, including secondary necrosis [32].
In addition, calcein AM (CAM), Live/Death, neutral red, CellTiter®, Aqueous One (96 AQ), Alamar Blue (AB), CellTiter-Blue® (CTB), CytoToxOne™, and flow cytometry were used to determine their utility in nanoparticle toxicity evaluation. In the cited study, it was found that the results of the assay that depended on direct staining of cells were difficult to interpret, because of dye interactions with NPs. The 96 AQ assay proved optimal for NP analysis. The results were not significantly altered by interactions between the test factor and reagents in the assay [16].
Herzog et al. [33] suggested the clonogenic assay to determine real cytotoxic effect on cell cultures due to the false results (positive or negative) that may occur in NP testing. The clonogenic assay (colony formation assay) is based on the ability of a single cell to form a colony. The latter study was based on the ability of A549, BEAS-2B (normal human bronchial epithelial cells) and HaCaT (normal human keratinocytes) cells to form colonies after 7 (for HaCaT cells) and 10 (for A549 and BEAS-2B) days of incubation with SWCNT (HiPco®). The EC50 comparison showed that the A549 cell line was more resistant than the other two lines. On the other hand, the analysis based on colony size showed that A549 was more sensitive than HaCaT cells. Although the clonogenic assay provided more accurate results than colorimetric tests, it did not become popular because it was too time-consuming for rapid toxicity screening [19, 33].
Nanomaterials are intensively studied as promising candidates for biomedical applications (e.g., targeted delivery of therapeutic drugs and medical imaging) with a purpose of eventual human administration [34]. NP design for medical applications should not only meet requirements, such as biocompatibility and biodegradability, but also site-specific delivery, long blood circulation and high cargo loading capacity [35]. Different nanomaterials show unique physical and chemical properties that depend, among others, on the type of materials (e.g., Au or Ag, Fe3O4, graphene and graphene oxide), hydrodynamic size, surface charge and aggregation behaviour and have been found to interact, often immediately (within seconds), after contact with biological systems, such as blood or tissue [34, 36, 37]. Nanoparticle aggregation via electrostatic screening can occur in complex aqueous mixtures of cell culture media that contain electrolytes, proteins, lipids and metabolites (highly ionic environment) [11, 38].
NPs at higher concentrations tend to form aggregates (agglomerates) under artificial conditions of
The protein layer of several nanometres on particle surface is called protein corona and it can be divided into a peripheral
Structure of protein corona [
Characteristic features of hard (HC) and soft corona (SC) [46].
Protein corona formation strongly affects cellular uptake mechanism, cell-nanoparticle interactions, intracellular location as well as cellular response (e.g., biocompatibility) [34, 35, 44]. The protein corona on the NP surface is hypothesised to hinder interactions of nanoparticle ligands and the targets on the cell surface [44, 47].
The study of Mirshafiee et al. [44] found that the protein corona formed on BCN-NPs (NPs functionalized with bicyclononyne) incubated in medium with 10% serum and 100% serum consisted of abundant proteins, such as chain A, a novel allosteric mechanism in haemoglobin, fetuin, haemoglobin foetal subunit beta or apolipoprotein A-II precursor. It was also reported that ≥88% of proteins in BCN-NP coronas had a molecular weight below 30 kDa. Even relatively low molecular weight proteins created corona that significantly reduced NP targeting efficiency [44]. Single-walled carbon nanotubes (HiPco®) were also found to interact with cell culture medium and its components. Casey et al. described that SWCNT interacted with the medium via physisorption through van der Waals forces [26, 48].
The process of protein corona formation has a decisive influence on nanoparticle-induced toxicity. For example, silica nanoparticles (AmSil30) precoated with human plasma caused lower cell-death induction in primary human endothelial cells and microvascular endothelial cell line (ISO-HAS1). The resulting effect was dependent on the time of corona formation. The most significant effect was recorded for the early corona, but prolonged incubation with plasma (>30 min) did not counteract membered toxicity [49]. In another example, thrombocytes were used to study the protein corona effect on the biological model. In the latter study, nanoparticles exposed to human plasma for 0.5 min did not activate thrombocytes to form aggregates due to the presence of the plasma protein corona [49]. The impact of protein corona formation on cellular uptake and dispersion state of nanoparticles after exposure to plasma was also investigated. It was found that NPs were monodispersed after short-time exposure (<10 min), whereas aggregates started to form during prolonged exposure (>30 min), but the tendency to form aggregates was mostly dependent on physicochemical properties of NPs. However, Tenzer et al. [49] did not describe negative effects of AmSil30 precoated with the protein plasma corona. Biological effects of protein-NPs were analysed using two lines: HeLa and U937 [43, 50]. The study conducted by Maiorano et al. [50] demonstrated that AuNPs incubated in two different culture media (DMEM and RPMI) exhibited different protein coronas. RPMI-treated NPs had less prominent protein coronas and, as a consequence, induced stronger toxicity of HeLa and U937 cells [50]. The study of Gräfe et al. [34] reported that the presence of the protein corona reduced the interaction of human brain microvascular endothelial cells (HBMEC) with magnetic nanoparticles coated with PEI (polyethylenimine) during 30 min of incubation [34].
Nanoparticle-induced pathological effects, such as cell death, coagulation, thrombocytosis or cytotoxicity, are also dependent on the type of NPs, but selected cellular model is also crucial in this kind of experiments [49, 51]. For example, polystyrene-based NPs (PS) with different PS-COOH and PS-PO3 groups coated with the serum protein were effectively taken up by both exposed cell lines (HeLa and hMSCs). NPs with PS-NH2 and PS-SO3 groups showed lower uptake by both cell lines [51].
The composition of protein corona was analysed using various methods and it was demonstrated that albumin, immunoglobulin G (IgG), fibrinogen and apolipoproteins were present in the corona of all the analysed nanoparticles [43]. Corona identification and composition analysis (Table 3) provide not only information about its complexity, conditions of PC formation and physicochemical features but also data on toxicity, cellular interactions and uptake, targeting and finally the usefulness in nanomedicine [46].
Feature | Techniques for PC analysis |
---|---|
Isolation of NPs-PC | Centrifugation, size exclusion chromatography (SEC), magnetic separation/magnetic flow field fractionation (MgFFF) |
PC structure analysis | Dynamic light scattering (DLS), differential centrifugal sedimentation (DCS), transmission electron microscopy (TEM) |
Protein quantitation | Bicinchoninic acid (BCA) assay, Bradford assay, thermogravimetric analysis (TGA) |
Binding affinity/stoichiometry and protein interaction | Fluorescence correlation spectroscopy (FCS), size exclusion chromatography (SEC), isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), quartz crystal microbalance (QCM), Z-potential measurement, |
PC composition | One-dimensional gel electrophoresis (1-DE or SDS-PAGE), two-dimensional gel electrophoresis (2-DE), mass spectrometry (MS) |
Analytical methods for corona evaluation [46].
For example, Urbas et al. [52] demonstrated that three types of nanoparticles, NPs-GO, Fe3O4, and GO-Fe3O4, displayed the ability to deplete various quantities of serum proteins from culture media (Figure 3). Graphene oxide and nanocomposite GO-Fe3O4 showed an increase in protein adsorption from culture medium. The results of the bicinchoninic acid (BCA) assay indicated different capacities of NPs to adsorb proteins in cell cultures [52].
Protein adsorption onto tested NPs after 48-h incubation period in complete cell growth medium [
Protein corona composition is also known to affect nanoparticle-cell interactions and biological fate of nanomaterials in cells. Gunawan and co-authors characterised the term ‘biological fate’ as describing the subcellular localisation of NPs and the distribution of NPs to specific organs
Other results described various biological responses of different cell types to NPs with protein corona layers [53]. Single-walled carbon nanotubes preferentially bound IgM relative to IgG on PEG-SWCNTs due to the surface charge and the conformation of surface functional groups (PEG); this resulted in higher accumulation of the aforementioned NPs in the liver compared to the spleen [55]. Poly(D,L-lactide)-based NPs showed interaction of surface functional group (covalently conjugated with apoB100 antibody) with LDL and were highly accumulated by liver macrophages [56]. Solid lipid nanoparticles (SLNs) modified with PEG induced the ABC phenomenon (accelerated blood clearance) upon repeated injections in mice and beagles. Moreover, PEGylated SLNs promoted liver/spleen uptake of NPs [57].
The application of polyethyleneglycol (PEG) for nanoparticle modifications reduces (but not totally suppresses) nonspecific protein corona formation [35, 51]. On the other hand, zwitterionic NPs were described to lack the protein corona [51].
The use of different nanomaterials for biomedical applications is indispensably associated with wide physico-chemical and biocompatibility analyses. The analysis of the effect of nanomaterials on different types of cells in various experimental conditions is an essential step in assessing the response of biological models (
Transmission electron microscopy of mSiO2 (‘contr’ – control sample) and mSiO2 incubated in PBS, for 24 (a), 48 (b) and 96 h (c, d) [
Evidence of nanostructure biodegradation of the sandwich-like mesoporous silica flakes has also been confirmed in another study. After 48-h incubation, the whole surface of silica nanoflakes was covered with cavities and was entirely destroyed [59]. The mechanism of silica dissolution is based on two simultaneous processes—degradation and re-deposition of silica on nanoparticle surface. Moreover, the effect of “self-healing” defects between both Si─O─Si bonds of double-linked Si atoms explains the very low rate of dissolution at the point of zero net proton charge (PZPC) of the surface [60].
A similar effect of PSB incubation on mesoporous silica nanospheres was observed by Yamada and co-workers [61], as these authors found that the mSiO2 porous structure was degradable after 2-day incubation in PBS. After 3-day incubation, mSiO2 displayed size and shape degradation with the final shape deformation and collapse of structures [61]. Another study based on core-shell magnetic mesoporous silica nanoparticles presented comparable results. Silica mesoporous hollow shells immersed in PBS for 2 days displayed structure deformation and additional cavities, whereas 8-day incubation showed complete degradation and coagulation resulting in new structure formation [62]. The erosion of mesoporous silica nanosphere structure modified with titanium dioxide was also observed in contact with
Phenotype is the effect exerted by molecules (e.g., drugs, nanoparticles, etc.) on a cell, tissue or whole organism; thus, the phenotype screening provides a holistic analysis that usually is more comprehensive than the sum of its parts. “
Phenotype MicroArrays™ (PMs) are a combination of microplate reader (that can measure OD every 1 min over few hours and provide information about kinetics of carbon energy reactions in a selected cell model) and microscopic modules equipped with fluorescence, brightfield, colour brightfield and phase contrast microscopy (for scanning changes in cell morphology during experiments). Phenotypic assays deliver more information and provide better understanding of the metabolic and cytotoxic effect of test substances [65]. Multiplex arrays can generate information on the use of energy pathways (based on the application of different nutrition analyses, PM-M1 to M4), effects of ions (PM-M5), hormones, metabolic effectors (PM-M6 to M8) and anti-cancer agents (PM-M11 to M14) (Table 4), cell number, cell health (based on cell health monitoring using phase contrast microscopy and kinetic determination of cellular energy) and apoptotic induction (via cell subpopulation analysis—examination of the increase in circularity due to cell shrinkage and cytoplasm condensation and lower phase signal exhibition) [65]. PMs can be used in genotype/phenotype analyses, cell line characterisation, metabolic reprogramming, cellular phenotype stability, Warburg effect, cell differentiation or bioprocess development [64]. Well-characterised model cell lines (e.g., HepG2, C3A, Colo205, A549, PC-3, IMR90, HL-60 or CEM) with defined metabolic properties can be used with the PM system to determine specific effects of nanomaterials on selected cell lines and to accurately identify the mechanism involved in the NP effect (e.g., mitochondrial toxicology) on the living system [66]. Array wells coated with different substances and combined with the redox assay (MA or MB redox dyes to measure cell energy [NADH] changes) are used for phenotypic determination. Comparison of two cell lines is visualised by bioinformatic software that highlights differences in recorded phenotypes (Figure 5) [64, 67].
Phenotype MicroArrays™ | Feature | Substrates/agents |
---|---|---|
PM-M TOX1 (Biolog) | Effect of a tested factor on energy production (mitochondrial toxicity) | Eight different carbon source: α-D-glucose, inosine, D-galactose, D-glucose-1-phosphate, xylitol, α-ketoglutaric acid, D,L-β-hydroxybutyric acid, pyruvic acid |
PM-M1 (Biolog) | Energetic substrate array | Carbon and energy sources (simple sugars, polysaccharides, carboxylic acids): cyclodextrin, dextrin, glycogen, maltitol, maltotriose, D-maltose, D-trehalose, D-cellobiose, gentiobiose, D-glucose-6-phosphate, D-glucose-1-phosphate, L-glucose, D-glucose, 3-O-methyl-D-glucose, methyl-D-glucoside, D-salicin, D-sorbitol, N-acetyl-D-glucosamine, D-glucosaminic acid, D-glucuronic acid, chondroitin-6-sulphate, mannan, D-mannose, methyl-D-mannoside, D-mannitol, N-acetyl-β-D-mannosamine, D-melezitose, sucrose, palatinose, D-turanose, D-tagatose, L-sorbose, L-rhamnose, L-fucose, D-fucose, D-fructose-6-phosphate, D-fructose, stachyose, D-raffinose, D-lactitol, lactulose, α-D-lactose, melibionic acid, D-melibiose, D-galactose, α-methyl-D-galactoside, N-acetyl-neuraminic acid, pectin, sedoheptulosan, thymidine, uridine, adenosine, inosine, adonitol, L-arabinose, D-arabinose, β-methyl-D-xylopyranoside, xylitol, myo-inositol, meso-erythritol, propylene glycol, ethanolamine D,L- α-glycerol-phosphate, glycerol, citric acid, tricarballylic acid, D,L-lactic acid, methyl D-lactate, methyl pyruvate, pyruvic acid, α-keto-glutaric acid, succinamic acid, succinic acid, mono-methyl succinate, tricarballylic acid, L-malic acid, D-malic acid, meso-tartaric acid, acetoacetic acid (a), γ-amino-N-butyric acid, α-keto-butyric acid, α-hydroxy-butyric acid, D,L-β-hydroxy-butyric acid, γ-hydroxy-butyric acid, butyric acid, 2,3-butanediol, 3-hydroxy-2-butanone, propionic acid, acetic acid, hexanoic acid |
PM-M2 (Biolog) | Energetic substrate array | Carbon and energy sources/nitrogen sources (protein-derived nutrients, primarily amino acids, dipeptides): Tween 20, Tween 40, Tween 80, gelatin, L-alaninamide, L-alanine, D-alanine, L-arginine, L-asparagine, L-aspartic acid, D-aspartic acid, L-glutamic acid, D-glutamic acid, L-glutamine, glycine, L-histidine, L-homoserine, hydroxy-L-proline, L-isoleucine, L-leucine, L-lysine, L-methionine, L-ornithine, L-phenylalanine, L-proline, L-serine, D-serine, L-threonine, D-threonine, L-tryptophan, L-tyrosine, L-valine, Ala-Ala, Ala-Arg, Ala-Asn, Ala-Asp, Ala-Glu, Ala-Gln, Ala-Gly, Ala-His, Ala-Ile, Ala-Leu, Ala-Lys, Ala-Met, Ala-Phe, Ala-Pro, Ala-Ser, Ala-Thr, Ala-Trp, Ala-Tyr, Ala-Val, Arg-Ala (b), Arg-Arg (b), Arg-Asp, Arg-Gln, Arg-Glu, Arg-Ile (b), Arg-Leu (b), Arg-Lys (b), Arg-Met (b), Arg-Phe (b), Arg-Ser (b), Arg-Trp, Arg-Tyr (b), Arg-Val (b), Asn-Glu, Asn-Val, Asp-Ala, Asp-Asp, Asp-Glu, Asp-Gln, Asp-Gly, Asp-Leu, Asp-Lys, Asp-Phe, Asp-Trp, Asp-Val, Glu-Ala, Glu-Asp, Glu-Glu, Glu-Gly, Glu-Ser, Glu-Trp, Glu-Tyr, Glu-Val, Gln-Glu, Gln-Gln, Gln-Gly, Gly-Ala, Gly-Arg, Gly-Asn, Gly-Asp, α-D-glucose |
PM-M3 (Biolog) | Energetic substrate array | Carbon and energy sources/nitrogen sources (dipeptides): Gly-Gly, Gly-His, Gly-Ile, Gly-Leu, Gly-Lys, Gly-Met, Gly-Phe, Gly-Pro, Gly-Ser, Gly-Thr, Gly-Trp, Gly-Tyr, Gly-Val, His-Ala, His-Asp, His-Glu, His-Gly, His-His (c), His-Leu, His-Lys (d), His-Met, His-Pro, His-Ser, His-Trp, His-Tyr, His-Val, Ile-Ala, Ile-Arg (b), Ile-Asn, Ile-Gln, Ile-Gly, Ile-His, Ile-Ile, Ile-Leu, Ile-Met, Ile-Phe, Ile-Pro, Ile-Ser, Ile-Trp, Ile-Tyr, Ile-Val, Leu-Ala, Leu-Arg (b), Leu-Asn, Leu-Asp, Leu-Glu, Leu-Gly, Leu-His, Leu-Ile, Leu-Leu, Leu-Met, Leu-Phe, Leu-Pro, Leu-Ser, Leu-Trp, Leu-Tyr, Leu-Val, Lys-Ala (d), Lys-Arg (b), Lys-Asp, Lys-Glu, Lys-Gly, Lys-Ile (b), Lys-Leu (b), Lys-Lys, Lys-Met (e), Lys-Phe, Lys-Pro, Lys-Ser, Lys-Thr, Lys-Trp (b), Lys-Tyr (b), Lys-Val (d), Met-Arg (b), Met-Asp, Met-Gln, Met-Glu, Met-Gly, Met-His, Met-Ile, Met-Leu, Met-Lys (e), Met-Met, Met-Phe, Met-Pro, Met-Thr, Met-Trp, Met-Tyr, Met-Val, Phe-Ala, Phe-Asp, Phe-Glu, α-D-glucose |
PM-M4 (Biolog) | Energetic substrate array | Carbon and energy sources/nitrogen sources (dipeptides): Phe-Gly, Phe-Ile, Phe-Met, Phe-Phe, Phe-Pro, Phe-Ser, Phe-Trp, Phe-Tyr, Phe-Val, Pro-Ala, Pro-Arg (b), Pro-Asn, Pro-Asp, Pro-Glu, Pro-Gln, Pro-Gly, Pro-Hyp, Pro-Ile, Pro-Leu, Pro-Lys (b), Pro-Phe, Pro-Pro, Pro-Ser, Pro-Trp, Pro-Tyr, Pro-Val, Ser-Ala, Ser-Asn, Ser-Asp, Ser-Glu, Ser-Gln, Ser-Gly, Ser-His (b), Ser-Leu, Ser-Met, Ser-Phe, Ser-Pro, Ser-Ser, Ser-Tyr, Ser-Val, Thr-Ala, Thr-Arg (f), Thr-Asp, Thr-Glu, Thr-Gln, Thr-Gly, Thr-Leu, Thr-Met, Thr-Phe, Thr-Pro, Thr-Ser, Trp-Ala, Trp-Arg, Trp-Asp, Trp-Glu, Trp-Gly, Trp-Leu, Trp-Lys (e), Trp-Phe, Trp-Ser, Trp-Trp, Trp-Tyr, Trp-Val, Tyr-Ala, Tyr-Gln, Tyr-Glu, Tyr-Gly, Tyr-His, Tyr-Ile, Tyr-Leu, Tyr-Lys, Tyr-Phe, Tyr-Trp, Tyr-Tyr, Tyr-Val, Val-Ala, Val-Arg, Val-Asn, Val-Asp, Val-Glu, Val-Gln, Val-Gly, Val-His, Val-Ile, Val-Leu, Val-Lys, Val-Met, Val-Phe, Val-Pro, Val-Ser, Val-Tyr, Val-Val, α-D-glucose |
PM-M5 (Biolog) | Ions: NaCl, ammonium chloride, sodium selenite, potassium chloride, calcium chloride, manganese chloride, zinc chloride, copper (II) chloride, cobalt chloride, iodine, sodium phosphate, sodium sulphate, sodium molybdate, sodium tungstate, sodium orthovanadate, potassium chromate, sodium pyrophosphate, sodium nitrate, sodium nitrite, lithium chloride, ferric chloride, magnesium chloride | |
PM-M6 (Biolog) | Hormone and metabolic effectors: dibutyryl-cAMP, 3-isobutyl-1-methylxanthine, caffeine, epinephrine, norepinephrine, L-leucine, creatine, triiodothyronine, thyroxine, dexamethasone, hydrocortisone, progesterone, β-estradiol, 4,5α-dihydro-testosterone, aldosterone | |
PM-M7 (Biolog) | Hormone and metabolic effectors: insulin, resistin, glucagon, ghrelin, leptin, gastrin, exendin-3, hGH (somatotropin), IGF-I, FGF-1 (aFGF), PDGF-AB, IL-1β, IL-2, IL-6, IL-8 | |
PM-M8 (Biolog) | Hormone and metabolic effectors: (Arg8) – vasopressin, parathyroid hormone, prolactin, calcitonin, calcitriol (1α,25-dihydroxyvitamin D3), luteinizing hormone (LH), luteinizing hormone releasing hormone (LH-RH), chorionic gonadotropin human (HCG), adrenocorticotropic hormone human (ACTH), thyrotropic hormone (TSH), thyrotropin releasing hormone acetate salt (TRH), IFN-γ, TNF-α, adenosine, Gly-His-Lys acetate salt | |
PM-M11 (Biolog) | Anti-cancer agents: solasodine, rotenone, aklavine hydrochloride, deguelin(−), celastrol, juglone, sanguinarine sulphate, dactinomycin, methylmethane sulfonate, azathioprine, busulfan, aclarubicin, chloramphenicol, chloroquine diphosphate, cyclophosphamide, diethylcarbamazine citrate, emetine, fluorouracil, hydroxyurea, mechlorethamine, mercaptopurine, quinacrine hydrochloride, streptozosin | |
PM-M12 (Biolog) | Anti-cancer agents: tamoxifen citrate, thioguanine, acriflavinium hydrochloride, pentamidine isethionate, mycophenolic acid, aminopterin, berberine chloride, emodin, puromycin hydrochloride, neriifolin, 5-fluoro-5′-deoxyurldine, carboplatin, cisplatin, zidovudine (AZT), azacytidine, cycloheximide, azaserine, p-fluoro-phenylalanine, dimethylhydrazine hydrochloride, phenethyl caffeate (CAPE), camptothecin, amygdalin, ellagic acid | |
PM-M13 (Biolog) | Anti-cancer agents: monocrotaline, altretamine, carmustine, mitoxantrone hydrochloride, urethane, thiotepa, thiodiglycol, pipobroman, etanidazole, semustine, gossypol, formestane, ancitabine hydrochloride, nimustine, aminolevulinic acid hydrochloride, picropodo-phyllotoxin, beta-peltatin, perillyl alcohol, dibenzoylmethane, 6-amino nicotinamide, carmofur, indole-3-carbinol, rifaximin | |
PM-M14 (Biolog) | Anti-cancer agents: cepharanthine, 4′-demethyl epipodophyllotoxin, miltefosine, elaidyl phosphocholine, podofilox, colchicine, methotrexate, acivicin, floxuridine, lefunomide, rapamycin, 13-cis retinoic acid, all-trans retinoic acid, piceatannol, (+)-catechin, mitomycin C, cytosine-beta-D-arabinofuranoside, daunorubicin hydrochloride, doxorubicin hydrochloride, etoposide, nocodazole, quercetin dihydrate, vinblastine sulphate |
Array examples [65].
Schematic visualisation that highlights differences in recorded phenotypes [
For example, Phenotype MicroArrays™ (PM-M TOX1 Plate Energetic Substrate Assay, 96-well microplate coated with eight different oxidisable carbon sources—each of the eight nutrition sources coated on one of eight rows on a microplate) give the possibility to screen cell-based energetic phenotype in a target cell model, for example, the MDA-MB-231 RFP breast cancer cell line, using different cellular nutrition sources (e.g., α-D-glucose, inosine, D-galactose, D-glucose-1-phosphate, xylitol, α-ketoglutaric acid, D,L-β-hydroxybutyric acid or pyruvic acid). This kind of multiplex analysis provides information on cell morphology, metabolic activity (metabolic pathway activity), sensitivity in response to particular energetic additives and the final cellular genetic background characterisation. The addition of an apoptotic agent (e.g., oridonin), chemical inhibitor or stimulator provides an opportunity to evaluate the potential mechanism regulating the energy pathway [65, 66]. Another example of PM application was presented by Bochner et al. [68]. Based on four phenotypic assays (PM-M1 to M4, containing 367 substrate nutrients), different human cancer cell lines, including HepG2/C3A, HepG2, Colo 205, A549, PC-3, HL-60 and CCRF-CEM and two murine white and brown adipocyte cell lines were analysed to determine energy-producing pathways. The results showed that human cancer cell lines exhibited distinct metabolic activity profiles. Moreover, white and brown adipocyte cell lines also had different profiles of energetic activity; metabolic fingerprints were established in all cell lines [68]. Similarly, human endothelial cells from the coronary artery (HCAEC), umbilical vein (HUVEC) and normal lung fibroblasts (NHLFs) were selected for cellular metabolism monitoring also with the use of phenotypic assays (PM-M1 to M4). The results obtained in this study demonstrated that all three cell lines strongly utilised adenosine, inosine, D-mannose and dextrin. HCAEC also metabolised mannan, pectin, gelatine and tricarballylic acid, while the HUVEC cell line did not exhibit the ability to metabolise any other unique substrates. NHLFs were able to additionally utilise sugars and carboxylic acids [69].
The profiling of human normal and cancer cells was also conducted by Parmar et al. [70]. HEK293, OV90, TOV112D, KLE, MES-SA and SKBR cell lines were selected to determine differences in response to anti-cancer agents using PM (PM-M11 to M14) and the effect of these agents on the mTOR signalling pathway by measuring S6 kinase (S6K) level. From a wide range of anti-cancer drugs, celastrol was found to inhibit the growth of SKBR, MESA-SA and TOV11D and target the mTOR signalling pathway [70]. In another study, Martinez-Reyes et al. [71] reported that mitochondrial metabolism was necessary for histone acetylation, hypoxia-inducible transcription factor (HIF-1) activation and proliferation based on WT-POLG and DN-POLG-HEK293 cell lines [71].
The application of PMs in nanotechnology is only a matter of time, thanks to the efficient and rapid determination of precise sites and modes of action of the tested substances. PMs provide a possibility to compare specificities of the study agents (e.g., drug and nanomaterial-drug conjugates) and the effect of the agent and its side effects. Finally, the PM system can be used for drug interactions or drug-nanomaterial analysis [67, 72].
The limitations of large-scale phenotyping techniques, including PM analysis, are related to the characteristics of all cells. PMs will not reveal the phenotypes of all cells, because cells have many phenotypes that are dependent on their environments. Different cells are constantly adapting in various ways to culture (environment) changes by altering their gene-expression pattern, protein content, membrane and cytoskeleton constitution and surface receptors. Moreover, the PM system will likely not record phenotypes that specifically involve intracellular structures (e.g., cytoskeleton, organelles or surface structures). In addition, the effect of some genes might be cryptic and the function of those genes only occurs under highly specific conditions; thus, it cannot be always determined in conditions provided by PM cultures [73].
Another approach to phenotypic screening is focused on microarray-based three-dimensional (3D) systems. 3D culture models may better mimic the
Holographic (transmission) microscopy is a high-resolution imaging technique that provides label-free and non-invasive, non-phototoxic and non-destructive method for real-time live cell culture analysis [76]. This type of microscopy allows for quantitative and qualitative measurements of living cells (not only cultures of mammalian cells, but also protozoan, bacterial and plant cells) and collecting information about cell surface area, cell viability and morphological changes, such as differentiation, proliferation, motility, cell death, confluence or cell segmentation (calculated from a particular hologram) [77, 78, 79, 80]. Traditional brightfield microscopy has some limitations, such as difficulties in visualising individual cells due to their low contrast properties, whereas DH microscopy provides possibility to determine cell number directly in cell culture vessels [81]. The size of the HoloMonitor™ M4 (Phase Holographic Imaging AB, Lund, Sweden) makes it possible to place it in a cell culture incubator, so that cell observations can be conducted over long periods of time without any changes in cell culture conditions [78]. Digital holographic microscopy also enables the formation of three-dimensional (3D) images of the observed objects.
The presented technique is based on the phase shift (ϕ) of the probing laser light (or other coherent light source) that can be reflected or transmitted through the monitored object. The illuminating light is split into two beams (differing in phase): an object beam and a reference beam [78, 81]. The reference beam remains undisturbed, while the object beam is shifted in phase by the object [79]. Next, the object beam is re-joined and interferes with the reference beam and creates a hologram that is recorded on a digital image sensor (CCD or CMOS) [77, 81]. The total phase shift can be translated into optical thickness (
Holographic phase imaging is an excellent tool for cell morphometric characterisation and cell migration studies. This technique has recently been applied in clinical diagnostics, e.g., screening for malaria infection of erythrocytes, cancer cell analyses or sperm quality [79]. Interest in the use of DH microscopy in research is constantly increasing. For example, Lajkó et al. [82] analysed the effect of a drug based on GnRH-III (gonadotropin-releasing hormone-III) on melanoma cells. Holographic phase imaging was used to visualise the migratory behaviour of melanoma cells in response to daunorubicin (Dau) coupled with GnRH-III and its derivatives (modified at position 4 with Lys(Ac) (conj1) or Lys(nBu) (conj2)). Cell migration analysis showed increased migration activity when cells were exposed to conj1, whereas conj2 decreased melanoma cell activity and exerted an immobilising effect on tumour cell spreading; thus, it was a better candidate for targeted tumour therapy [82]. Monitoring of HeLa cancer cells and MC3T3-E1 preosteoblast cells via holographic technique was also conducted by Peter et al. [78]. These authors evaluated cell movements and morphological parameters of cells in two experiments. In the first one, the HoloMonitor™ M4 was used to detect the effect of EGCg (green tea—epigallocatechin gallate) on HeLa cell motility. Time-lap images showed that migration, motility and the speed of motility were reduced after EGCg was added to the culture. The second experiment involved MC3T3 plated on transparent titanate nanotubes (TNT) surface and the impact on adhesion and spreading process of the cells was demonstrated using the HoloMonitor. The authors have concluded that holographic digital microscopy is a useful tool for cellular behaviour analysis, but some limitations have also been found. Peter et al. [78] observed that under certain thicknesses, some parts of the cells (e.g., parts of the thin lamellipodium) slicked into the background surface. It was caused by the limited vertical resolution of the optical system [78].
In our study, the effect of the h-BN-Au nanocomposite on L929 and MCF-7 cell lines was analysed during 12-h incubation using the HoloMonitor™ M4. L929 cells did not show any significant differences in the presence of the nanocomposite and the doubling time (DT) value was similar to DT obtained in the control culture (Figure 6). The results obtained for the MCF-7 cell line incubated with h-BN-Au demonstrated a stronger effect on cells. The DT analysis using holographic technique indicated a high reduction of proliferation capacity (the DT value for the MCF-7 control sample was 25.95 h, whereas for experimental cultures, it was 469.9 h) [83].
The morphology of the L929 and MCF-7 cell lines incubated with the h-BN-Au nanoparticles. L929 culture time-points at 0 h (A); at 12 h (B); MCF-7 culture time-points at 0 h (C); at 12 h (D) [
Atomic force microscopy (AFM) is based on a laser reflected off a cantilever onto a scanning surface of the examined object and quantitative information about surface morphology and cell spread is collected.
AFM is a crucial technique for determining cell interactions on the surface of the tested material. If material exhibits high biocompatibility, the surface of the material will allow cells to attach (interaction between cell-surface integrin receptors) and adsorb extracellular matrix (ECM) proteins. Surface properties, such as wettability, roughness or surface charge, are important for cellular attachment and lamellipodium/filopodium formation. The AFM measurement provides information on cellular morphology changes and lamellipodium/filopodium permissiveness. The measurement of atomic force microscopy of living cells can be performed in PBS and provides information on cell height, total cell surface area, attachment angle and extension of lamellipodia/filopodia. It is also possible to measure fixed cell (in 4% paraformaldehyde) topography and examine filopodia and lamellipodia. An interesting example is the analysis of H4 and PC12 cell lines plated on different materials—glass, polystyrene (PSt), silicon (Si), nanocrystalline diamond (NCD) and cubic silicon carbide (3C-SiC). In the latter study, AFM analysis demonstrated that the type of the surface determined cell height/area, attachment angle and the reduction of the lamellipodium/filopodium area. Cell-substrate interaction was different for H4 and PC12 cell lines, e.g., for H4 cells; the most negative interaction was recorded for glass, the most positive for 3C-SiC, while PC12 cells had the most negative interaction with glass, but the best with 3C-SiC and PSt. The authors concluded that AFM analysis indicated that neural cell interactions with 3C-SiC resulted in the optimal cell viability, morphology and interaction of cells with 3C-SiC surface [1]. Frewin et al. [1] published the results of AFM analysis concerning cellular interaction on graphene. The experiments focused on cytoskeleton organisation and the determination of the number of contact sites, and AFM technology can provide valuable information on the mechanism of cellular adhesion and proliferation on graphene surface. Different methods of graphene preparation, for example, mechanical cleaving, chemical synthesis and chemical vapour deposition (CVD) on metals or epitaxial growth on SiC, not only give graphene different electrical, optical or morphological properties, but also different biocompatibility. For example, the biocompatibility of a single graphene layer produced by CVD on Cu was higher in comparison with SiO2/Si surfaces studied on human osteoblasts and mesenchymal stem cells [1, 84]. In another study, epitaxially grown graphene films on (0001) 6H-SiC substrates were evaluated in cellular response experiments using AMF analysis. It was found that HaCaT (human keratinocytes) after 72-h culture on graphene and 6H-SiC surfaces exhibited similar morphology to cells cultured on the PSt control. On the other hand, the MTT assay suggested better biocompatibility for 6H-SiC than for the graphene surface. Moreover, different preparation of graphene surfaces (first one without any further surface treatment, and the second one additionally disinfected by immersion in ethanol) resulted in more homogeneous and increased cell adhesion on ethanol-sterilised graphene surface [1]. Our study also confirmed the undeniable value of AMF analysis in the experiment involving the MAC-T cell line seeded on different surfaces (glass, glass coated with poly-D-lysine) (Figure 7). In the aforementioned study, surface analysis and cell height analysis clearly exhibited differences in cell growth on the two surface variants [85].
AFM analysis of MAC-T cells: cell height on glass surface (A); cell height on glass coated with poly-D-lysine (B); 3D image of cell growing on glass surface (C); 3D image of cell growing on poly-D-lysine (D) [
Another notable study used the AFM technique not only for cell analysis after nanoparticle uptake, but also after exposure to rotating magnetic field (RMF). Observations of MCF-7 cells after 1.5-h incubation in 40 mT magnetic field revealed changes in cell surface, which was rougher with many small pore-like structures in comparison to untreated cells [86].
The present overview describes and compares widely used biocompatibility/cytotoxicity assays in nanomaterial studies. Due to the type of nanoparticles and their properties, applicability of popular assays used for engineered nanomaterial screening might be limited. The significant numbers of false-positive or false-negative signals are generated [16]. The tendency of nanoparticles to:
Interact and photocatalyse assay reagents,
Create agglomerate in the conditions of in vitro and in vivo environment,
Create protein layer of several nanometres on nanoparticle surface,
Degrade and deform in vitro environment,
affect the results obtained in popular assays, thus classic cytotoxicity assays alone are not sufficient to evaluate nanomaterial biocompatibility.
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