3.3.3. Energy Use per Private Passenger Kilometer (PKT)

Energy use per PKT is a more meaningful measure of energy consumption in public transport, which enables genuine comparisons to be made with private passenger transport energy use. Table 3 provides the energy consumption per PKT for private transport, and Figure 4 depicts the data for the Swedish and global sample. The European cities, including Freiburg, and especially the Swedish cities, are amongst the lowest energy consumers in cars, though there is a range in Sweden from 2.74 MJ/PKT in Jönköping down to 1.74 MJ/PKT in Umeå. The larger Swedish cities (2.35 MJ/PKT) are about the same as Freiburg (2.39) and the average for the European cities (2.30), while the smaller cities are little lower at 2.18 MJ/PKT. Compared to the Canadian (3.79 MJ/PKT), Asian (3.31), Australian (2.87) and American (2.85) cities, the Swedish cities are significantly less energy hungry in cars (2.27 MJ/PKT). Of course, this sets a greater challenge for public transport to compete in energy terms, especially where loadings in public transport vehicles are low.

**Figure 4.** Energy use per passenger kilometer (PKT) in private passenger transport in ten Swedish cities (2015); Freiburg (2015); and American, Australian, Canadian, European and Asian cities (2005–2006).


Frequency and Distribution of Pulpal Calcifications in Teeth Involved in Jaw Tumors

*María Teresa Hernandez-Solis, Edith Lara-Carrillo, Víctor Hugo Toral-Rizo, Ronell Eduardo Bologna-Molina, José Edgar Garduño-Mejía, Norma Guadalupe Ibáñez-Mancera, Wael Hegazy-Hassan and Ana Miriam Santillán-Reyes*

#### **Abstract**

Pulp calcifications are idiopathic mineralized masses associated with irritation, age, trauma, and systemic or genetic diseases. The objective of this work was to examine frequency and distribution of pulp calcifications in teeth involved in jaw tumors, analyzing their relationship with age, sex, location, size, and diagnosis of the lesion in a sample of 21 teeth associated with tumors of the jaws. Imaging analysis included CT scans, periapical X-rays, and orthopantomography of the clinical record; histological analysis included pulp tissue fixed in 10% buffered formalin for 24 h, with hematoxylin and eosin staining, and examined under light microscope. A chi-square test was applied to associate calcifications with all variables. The tumor lesions were from patients aged 17–66 years. Calcifications were observed in 38.1% of cases on image and histologically in 76.2%; 56% were nodular and 68.8% were distributed in chamber and root canal. The male sex presented a higher frequency of pulp calcifications, estimating a statistically significant difference with respect to women (p = 0.004); there was no statistical significance with the other variables. In conclusion, the pulp tissue of teeth affected by maxillary tumors presents a percentage of pulp calcifications similar to the tissue where the periradicular tissue is intact.

**Keywords:** pulpal calcifications, jaw tumors, pulpal histology, dental pulp, pulp stones

#### **1. Introduction**

Pulpal calcifications are masses of mineralized tissue that can develop freely in any area of the pulp tissue or be found adhered at the interface of the dentin and pulp of healthy or diseased, erupted, or unerupted teeth [1]. Morphologically, they can be nodular, oval, needle-like, or irregularly shaped and are predominantly composed of minerals such as hydroxyapatite, aluminum, copper, iron, potassium, lead, and zinc [2–4].

Previously published studies have reported a prevalence of 8–90%, and they can be located both in the pulp chamber and in the root canal; they can be single or multiple, and in terms of size, they can be tiny below 200 μm or so large that they can obliterate the pulp chamber or root canal [5–7].

According to their topographic location, Satheeshkumar et al. [8] classified them as follows: single pulp calcification in the pulp chamber (Type I), multiple pulp calcifications present in the pulp chamber (Type IA), single pulp calcification present in the root canal (Type II), multiple pulp calcifications present in the root canal (Type IIA), multiple pulp calcifications present in pulp chamber and root canal (Type IIB), and continuous calcifications extending from the pulp chamber to the root canal (Type III).

The etiological factors of this process are still unknown; however, they are associated with different factors, such as trauma, pulp degeneration, orthodontic treatment, periodontal disease, caries, operative procedures, pulp inflammation, systemic diseases, or genetic conditions [9–13]. This process used to be associated with age; however, it has been observed that they are also found in young patients and in teeth that have not yet erupted [14].

Investigations regarding pulpal calcifications have been carried out over time with different methodologies based on imaging studies that include various techniques, such as periapical X-ray, panoramic X-ray, bitewing X-ray, cone beam tomography, or micro-CT and histological studies. These methodologies have been performed on teeth present in the mouth, extracted dental organs, or prehistoric skeletal remains [15–17].

Tumor lesions are abnormal tissue that grows in both the maxilla and mandible; they are relatively rare and affect soft and hard tissues and may extend to the facial region. Most of them are benign, but they tend to be aggressive and grow exponentially, displacing bone tables and thus the teeth [18].

The aim of this work was to show the frequency and distribution of pulp calcifications of teeth involved in tumor lesions of the jaws by means of imaging and histological analysis, analyzing whether there is any relationship between pulp calcifications and age, sex, location, size, and diagnosis of the lesion.

#### **2. Materials and methods**

For this purpose, an analytical, descriptive, and cross-sectional study was designed with nonprobabilistic sampling by convenience. The sample consisted of 21 caries-free teeth with intact enamel involved in eight tumor lesions in patients between 17 and 66 years old, which were removed by the therapeutic indication of the maxillofacial surgeon. All donors signed the informed consent, in which it was mentioned that the teeth would be used for scientific research and the tissue obtained from the surgical maneuver would be processed for histopathological diagnostic purposes. In addition, this project was approved and registered by the Research Ethics Committee of the Autonomous University of the State of Mexico (2021/P11).

Immediately after surgical excision, the tumor lesion was immersed in 10% buffered formalin for immersion fixation and transferred to the oral pathology laboratory at the School of Dentistry of the Autonomous University of the State of Mexico for histological processing. The teeth were separated from the tumor lesion with a scalpel blade no. 15 in soft tissue and flexible diamond disc (Plexoflex Fine Grain. DFS-Diamon, Riedenburg, Germany) when the alveolar bone was involved.

#### *Frequency and Distribution of Pulpal Calcifications in Teeth Involved in Jaw Tumors DOI: http://dx.doi.org/10.5772/intechopen.109585*

The teeth separated from the tumor lesion were kept in 10% buffered formalin while pulp tissue was obtained; this process was performed by marking with a flexible diamond disc (Plexoflex Fine Grain. DFS-Diamon. Riedenburg, Germany) and abundant irrigation along the longitudinal axis of the uniradicular teeth. For the multiradicular teeth, two marks were made, one in the crown and the other in the root zone, removing the hard tissues and obtaining the pulp tissue from the chamber and root canal.

Immediately after the pulp tissue was obtained, it was placed again in 10% buffered formalin for 24 h and then dehydrated in a series of alcohols to be included in a paraffin block and stained with hematoxylin and eosin. The slides were obtained with 5 μm thick tissue sections.

To perform the histological analysis and topographical location with the classification of Satheeshkumary et al. [8], the slides were observed using a Leica Microsystems DM750 microscope at a magnification of 10x. The analysis was performed by two examiners from the Endodontics and Oral Pathology areas. Imaging was performed with Motic, VM 3.0, Digital Slide Scanning System using the programs Phatomation PMA.start (Pathomation BV, Berchem, Belgium) and ImageJ-FIJI.

For the imaging analysis, panoramic radiographs, periapical radiographs, and tomographies were collected and included in the clinical records, which were reviewed to determine the absence or presence of calcifications.

Subsequently, the statistical analysis of the data was carried out using SPSS package version 26 (IBM Corp. Armonk, N.Y. USA). The descriptive statistical data of variables were obtained, and Pearson's chi-square test was performed to associate the variables (age, sex, diagnosis, location, and size of the lesion) with the presence of pulpal calcifications.

#### **3. Results**

The sample consisted of 21 teeth, seven incisors (33.3%), two canines (9.5%), five premolars (23.8%), and seven molars (33.3%). They were from eight tumor lesions with histopathological diagnosis: two ameloblastomas (25%), two keratocysts (25%), one central giant cell lesion (12.5%), one peripheral giant cell lesion (12.5%), one calcifying epithelial odontogenic tumor (12.5%), one peripheral ossifying fibroma (12.5%), one peripheral giant cell lesion (12.5%), one calcifying epithelial odontogenic tumor (12.5%), and one peripheral ossifying fibroma (12.5%).

The donor patients were four women (50%) and four men (50%), ranging in age from 17 to 66 years, with a mean age of 34.75 years and a standard deviation of 20.76 years.

The location of the tumor lesions was 50% in the maxilla and 50% in the mandible, with a minimum size of 2 cm and a maximum of 15 cm, a mean of 7.43 cm, and a standard deviation of 4.04 cm. All teeth were analyzed together with their imaging studies included in the clinical records; 10 teeth were reviewed with tomography (46.6%), eight with panoramic radiographs (38.1%), and three with periapical radiographs (14.3%), observing calcifications in the imaging analysis in 38.1% of the cases (**Figure 1**). Sagittal view of a CT scan showing pulp calcification in the coronal area (white arrow) of a developing third molar associated with a keratocyst). Histological examination with hematoxylin and eosin revealed that pulp calcifications were present in 76.2% of the analyzed teeth. With respect to shape, 56.25% were only

#### **Figure 1.**

 *Sagittal view of a CT scan showing pulp calcification in the coronal area (white arrow) of a developing third molar associated with a keratocyst.*

#### **Figure 2.**

 *Microphotograph of circular (nodule) and elongated pulp calcifications in the pulp tissue of a tooth associated with peripheral giant cell lesion (hematoxylin and eosin, 100× magnification, Motic VM 3.0. Digital Slide Scanning System).*

nodules and 43.75% were nodules and needle-like in the pulp tissue itself ( **Figure 2** ). Microphotograph of circular (nodule) and elongated pulp calcifications in the pulp tissue of a tooth associated with peripheral giant cell lesion. Hematoxylin and eosin, 100× magnification, Motic VM 3.0. Digital Slide Scanning System).

*Frequency and Distribution of Pulpal Calcifications in Teeth Involved in Jaw Tumors DOI: http://dx.doi.org/10.5772/intechopen.109585*

Pulpal calcifications were distributed topographically according to the classification of Satheeshkumary et al. [8] as follows: 68.8% were in both the pulp chamber and root canal (Type IIB), 18.8% were multiple in the root canal (Type IIA) (**Figure 3**). Microphotograph of pulp tissue of a tooth involved in ameloblastoma, showing multiple calcifications of different sizes and shapes. Hematoxylin and eosin, 40× magnification, Motic VM 3.0. Digital Slide Scanning System), and 12.5% presented continuous calcifications from the crown to the root canal (Type III).

The presence of these calcifications was more frequent in males (87.5%) than in females (12.5%), showing a statistically significant difference with a value of *p* = 0.004.

In relation to age groups, more calcifications were observed in the 17- to 30-year-old group compared to the others, without showing statistically significant differences between groups (*p* = 0.028) (**Table 1**). It shows the frequency of pulpal calcifications in relation to age groups.

Pulp calcifications were found in 68.7% of mandibular teeth and 31.3% of maxillary teeth, but this difference was not statistically significant (*p* = 0.717).

Regarding the size of the tumor lesion and its relationship with calcifications, the 1 cm to 4 cm group had no calcified masses, while the 5 cm to 9 cm and 10 cm to 15 cm groups each had 8 teeth (50%); however, there was no significance between them (*p* = 0.131).

Regarding the histopathological diagnoses of the lesions and their relationship with calcifications, no significant association was found (*p* = 0.484), so the diagnosis

**Figure 3.**

*Microphotograph of pulp tissue of a tooth involved in ameloblastoma, showing multiple calcifications of different sizes and shapes (hematoxylin and eosin, 40× magnification, Motic VM 3.0. Digital Slide Scanning System).*

**Table 1.**

*Frequency of pulp calcifications in relation to age groups.*

**Table 2.**

*Frequency of pulp calcifications in relation to histopathological diagnoses of tumor lesions.*

does not determine the existence or absence of calcific precipitations (**Table 2**). It shows the frequency of pulp calcifications in relation to histopathological diagnoses of tumor lesions.

#### **4. Discussion**

The study of pulp calcifications has led to development research to determine the prevalence, distribution, and association with diseases such as caries, periodontal disease, or genetic conditions. However, in the literature review, no previous data were found on the study of pulp calcifications in teeth involved in maxillary tumors, so one of the objectives of this study was to publicize and disseminate the results, adding knowledge to this area.

Pulp calcifications can be detected through diagnostic means such as imaging and histological studies. Imaging studies are carried out by panoramic radiographs, periapical, bitewing, cone beam tomography, or micro-CT, which allow locating radiopaque nodules with a size greater than 200 μm since below this size they are not detectable by these means. For histological studies, they allow observing calcifications of different sizes and locations, since the lamellae are observed under the microscope with different magnifications, allowing the localization of these in any path of the pulp tissue.

Regarding the prevalence of pulp calcifications, previous studies have shown a range from 9.6 to 95% [3, 16]. These percentages vary due to the methodologies used for each investigation; usually, imaging studies show a lower frequency than histological studies since the lamellae are seen under the microscope, identifying any size of calcification. This finding agrees with our results and those of Huang et al. [19] since both studies performed imaging and histological analyses and observed similar results. Huang et al. [19] showed the presence of calcifications of 62% in the histological area and 30% in the radiological area, while our results were 76.2% in the histological area and 38.1% in the imaging area.

*Frequency and Distribution of Pulpal Calcifications in Teeth Involved in Jaw Tumors DOI: http://dx.doi.org/10.5772/intechopen.109585*

Histological studies allow a greater morphological appreciation of pulp calcifications, and we agree with Milcent et al. [2] that pulp calcifications are morphologically heterogeneous since they are different from each other in shape and size.

Another important factor is that the prevalence of calcifications in pulp tissue may be different depending on the ethnic group. For example, in Mexican patients, they have been observed in 84% [20], Peruvians 83.58% [21], Taiwanese 83.3% [22], Iranians 76% [23], Argentines 55% [24], Jordanians 51.4% [25], Turks 38% [26], and Yemenis 3.99% [13].

Sener et al. [24] and Ranjitkar et al. [1] performed the analysis of pulp calcifications with bitewing radiographs, finding a prevalence of 38% and 46.1%, respectively. In the present study, periapical, panoramic, and tomography radiographs were examined analyzing the coronal and radicular areas, and the percentage of calcifications was similar at 38.1%.

The frequency of pulp calcifications in males was higher than in females, which agrees with Hsieh et al. [23]. The possible cause is that men present greater dental attrition in relation to women, and the pressure exerted by the tumor in the apical area allows for premature contact points, which provides a local irritant in the pulp tissue.

Another interesting fact is that pulpal calcifications have been related to advanced age [9]. In contrast, in this study, the age group 17–30 years old was the one with the highest percentage of calcifications.

Mandibular teeth had a higher percentage of pulp calcifications, which agrees with Olivares et al. [20]. However, there are also studies where the maxillary dental organs are the predominant ones without a significant difference [24].

Regarding the size of the lesion and the histopathological diagnosis, no similar antecedents were found in the literature since these variables have not been investigated in pulp tissue under these conditions. Therefore, the present study generates knowledge that can be used as a basis for future lines of research.

However, one of the limitations of the study is the small size of the sample, since being a histological study, the samples of the tumor lesions should present dental organs, and these should be kept in an adequate fixation medium for the preservation of the pulp tissue, which is not frequent to find or to obtain them in the correct preservation medium.

#### **5. Conclusion**

In conclusion, the pulp tissue of teeth affected by maxillary tumors presents a similar percentage of pulp calcifications to studies where the periradicular tissue does not present any alteration.

Another important fact is that there was no statistically significant relationship between pulp calcifications and tumor size or histopathological diagnosis.

The results of this study may be useful as a basis for future lines of research since they broaden the knowledge of pulp calcifications and histological characteristics of pulp tissue of teeth in the presence of maxillary tumors. For future studies, it would be convenient to analyze this finding in a larger sample.

#### **Conflict of interest**

The authors declare no conflicts of interest.

## **Author details**

María Teresa Hernandez-Solis1 , Edith Lara-Carrillo2 \*, Víctor Hugo Toral-Rizo3 , Ronell Eduardo Bologna-Molina4 , José Edgar Garduño-Mejía5 , Norma Guadalupe Ibáñez-Mancera6 , Wael Hegazy-Hassan2 and Ana Miriam Santillán-Reyes2

1 Faculty of Dentistry, Doctoral Program in Health Sciences, Autonomous University of the State of Mexico, Toluca, Mexico

2 Center for Research and Advanced Studies in Dentistry "Dr. Keisaburo Miyata" Faculty of Dentistry, Autonomous University of the State of Mexico, Toluca, Mexico

3 Faculty of Dentistry, Orocentro Clinic, Autonomous University of the State of Mexico, Toluca, Mexico

4 Faculty of Dentistry, Center for Stomatological Molecular Pathology, Republic University, Montevideo, Uruguay

5 Department of Maxillofacial Surgery, Regional Hospital "Lic. Adolfo López Mateos", Toluca, Mexico

6 The Interdisciplinary Center of Health Sciences UST, Instituto Politécnico Nacional, Mexico City, Mexico

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Frequency and Distribution of Pulpal Calcifications in Teeth Involved in Jaw Tumors DOI: http://dx.doi.org/10.5772/intechopen.109585*

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## Aesthetic Smile Designing

*Monisha P. Khatri, Shreya Kishore and Srujana Hemmanur*

#### **Abstract**

'Smile is a universal language, shared by people all over the world'. It conveys a lot without saying anything at all. Our smile is of utmost importance and dental aesthetics play a vital role to create it. Smile designing (SD) consists of various components that aim to develop the overall personality of a patient. To create an aesthetic, smile is an organised and systematic approach that is required to evaluate, diagnose and resolve the problems associated with it. The ultimate goal of an aesthetic make-over is to ensure a stable masticatory system, where the oral hard and soft tissues remain in harmony. Hence this chapter aims to focus on various aspects of SD that includes its goals, components, procedure and future prospects.

**Keywords:** aesthetic, smile designing, golden proportion, gingival zenith, veneers

#### **1. Introduction**

The goal of smile designing is to create a harmonious balance between teeth, tissues, muscles, skeletal structures and joints while attending to the aesthetic requirement of the patient [1]. This requires complete understanding and knowledge of the symmetry, shape and proportions related to the hard and soft tissues of the oral cavity.

#### **2. Components of smile designing**

In dental treatment, aesthetics has traditionally been associated with profile enhancement. An organised and systematic approach is required to evaluate the aesthetic problems and diagnose and resolve them. The ultimate goal as clinicians is to achieve proportionate and pleasing composition in patients' smiles by creating an arrangement of various aesthetic elements. Harmonising an aesthetic smile requires an integration of facial and dental composition. The dental composition includes tooth components and gingival components, one of the vital elements of smile designing [1].

#### **2.1 Tooth components**

Tooth components consist of the following:

#### *2.1.1 Dental midline*

The dental midline is the vertical contact interface between the two maxillary central incisors. It is to be parallel to the midline of the face and perpendicular to the interpupillary line. Other landmarks that can help assess the dental midline are the midline of the nose, forehead and the philtrum of the upper lip. To evaluate the midline, one must consider the location and alignment. The dental midline should be parallel to the long axis of the face, perpendicular to the incisal plane, and should be over the papilla, that is the midline that should drop straight down from the papilla [1, 2].

#### *2.1.2 Incisal lengths*

The position of the maxillary incisal edge is the most important determinant in smile line as it acts as a reference point to decide the tooth proportions and the gingival levels. The parameters used to help establish the maxillary incisal edge positions are the amount of tooth display during smile, the phonetics and the patient input.

The amount of tooth display is determined when the mouth/muscles around the mouth are relaxed. Ideally, 3.5 mm of incisal third of the maxillary centrals are visible, which continues to reduce as the patient ages, due to loss in muscle tonicity.

Phonetics is a primary determinant, and the various phonetics used are (i) M sound, (ii) E sound, (iii) F and V sounds and (iv) S sound.

Patient input is an important guide to determine the smile line, as the patient's desire and satisfaction is the ultimate goal [1].

#### *2.1.3 Tooth dimensions*

Correct teeth proportions are essential in creating an aesthetically pleasing smile. Central dominance is a phenomenon that states that the centrals must be the dominant teeth in smile and should display pleasing proportions, as they are the key to an aesthetic smile. There are various guidelines for establishing correct proportions in an aesthetically pleasing smile, and they are as follows: [1, 3, 4].

#### i.*Golden proportion* (*by Lombardi* [1])

When viewed from the facial aspect, the width of each anterior is 60% of the width of the adjacent tooth. The mathematical ratio being 1.6:1:0.6 (**Figure 1**).

ii.*Recurring aesthetic dental proportions* (*by Ward* [1])

**Figure 1.** *Golden proportion based on apparent width from the frontal view.*

#### **Figure 2.** *Recurring aesthetic dental proportions.*

The successive width proportion when viewed from the facial aspect should remain constant as we move posteriorly from the midline. This theory offers greater flexibility to match tooth proportions with facial proportions (**Figure 2**).

```
iii.M proportions (by Methot [1])
```
M proportions compare the tooth width with the facial width using software on a computer, due to which, involves more scientific calculations rather than artistic analysis.

#### iv.*Chu's aesthetic gauges* [1]

Dr. Chu's research refutes the golden proportions. A series of gauges were made available to make the intra-oral analysis easier. The gauges allow fast and simple diagnosis of tooth discrepancies and are used as a reference guide between the clinician and the lab technician, which in turn reduces the incidence of communication errors.

#### *2.1.4 Zenith points*

The most apical position of the cervical tooth margin where the gingival is most scalloped is known as the zenith point (**Figure 3**). It is located distal to the vertical axis of the tooth, except for lateral incisors where it is centrally located. Establishing the proper location of the zenith point is the critical step in altering the mesial and distal dimensions [4].

#### *2.1.5 Axial inclinations*

Also known as tooth inclinations, it compares the vertical alignment of maxillary teeth to central vertical midline. From the maxillary centrals to the maxillary canines,

#### **Figure 3.** *Zenith points and their relation to the midline.*

there should be a progressive increase in the mesial inclination of each subsequent anterior tooth, which looks natural. The evaluation of the axial inclination can be done in the frontal view photograph of the anterior teeth. The guide for labiolingual inclination is as follows: (i) maxillary central incisor is positioned vertically or slightly labial. (ii) maxillary lateral incisal edge is inclined slightly labially. (iii) the maxillary canine cusp is angulated lingually [1, 4].

#### *2.1.6 Contact area and contact point*

Interproximal contact area (ICA) is defined as the broad zone in which two adjacent teeth touch (**Figure 4**). An increase in ICA helps to create an illusion of longer teeth, which in turn helps in eliminating black triangles [1].

Interproximal contact point (ICP) is the most incisal aspect of the interproximal contact area.

#### *2.1.7 Incisal embrasure*

The incisal embrasures are supposed to display a natural, progressive increase in size from the centrals to the canines, which results in the interproximal contact points moving more apically as we move from the centrals to the canines to mimic the smile line. Failure in providing adequate incisal embrasure results in making the teeth appear too uniform and in loss of the incisor's individuality [4].

#### **2.2 Gingival components**

This composes of the soft tissue component of smile designing and they are as follows:

#### *2.2.1 Gingival health*

It is of paramount importance that the gingival tissues are in proper health prior to the start of the treatment. Healthy gingiva usually exhibits the following characteristic features: (i) pale pink, stippled, firm in consistency, (ii) located 3 mm above the alveolar crestal bone and (iii) located interdentally, 5 mm above the inter-crestal bone, should be pointed and should fill the gingival embrasure right up to the contact area [5].

**Figure 4.** *Interproximal contact area.*

#### *2.2.2 Gingival levels and harmony*

Establishing the ideal gingival levels for each individual tooth is the key to creating a harmonious smile. The cervical gingival height of the maxillary centrals should be symmetrical and can match that of the canines. The gingival margin of the lateral incisor can be 0.5–2.0 mm short of the central incisors [5, 6].

#### *2.2.3 Smile line*

Smile line refers to an imaginary line along the incisal edges of the maxillary anterior teeth, which should mimic the curvature of the superior border of the lower lip while smiling.

Keep in mind that the lip line should not be confused with the smile line. It refers to the position of the inferior border of the upper lip during smile formation and thereby determines the display of tooth or gingiva. Showing 3–4 mm or more of the gingiva often requires cosmetic periodontal recontouring to achieve ideal results, as in cases of gummy smiles [1, 5].

#### **3. Treatment**

Treatment modalities include veneers, direct or indirect and digital smile designing with help of software tools and CAD/CAM.

#### **3.1 Veneers**

#### **Definition**

A veneer is a layer of tooth-coloured material that is applied to a tooth to restore localised or generalised defects and intrinsic discolouration, a conservative aesthetic restoration of anterior teeth to mask discolouration, restore malformed teeth, close diastemas and correct minor tooth alignment [7].

#### **History**

Veneers were developed originally in the 1930s. California dentist Charles Pincus [8] developed thin facings of air-fired porcelain that could be fastened in place with adhesive denture powder. In 1955, Buonocore's [8] research into the acid etch technique provided a simple method of increasing the adhesion to enamel surfaces for acrylic filling materials. In the 1970s, Faunce [8] described a one-piece acrylic resin prefabricated veneer as an improved alternative to direct composite resin bonding. Veneer was attached both chemically and mechanically. With the advent of materials like glass-infiltrated ceramics and zirconia techniques, the ease and precision with which veneers can be prepared have increased multi-folds [8].

#### **Classification**

1.On the basis of extent—Partial/Full

The partial veneers are the ones that partially cover tooth structure while full veneers encompass the full tooth structure with the veneer material.

2.On the basis of technique—Direct/Indirect

Direct application of composite material to create direct veneers is done while lab preparation of veneers using either composite or porcelain creates indirect veneers. 3.On the basis of material used—Composite/Porcelain

The use of different materials such as composite resin or porcelain are used to prepare veneers.

4.On the basis of mode of fabrication—Pre-fabricated/Custom made

Prefabricated veneers are the ones that are modified to fit any tooth size or shape while custom-made veneers are fabricated for a specific patient and are customised built.

5.On the basis of tooth preparation—(**Figure 5**) [9]

Class 0—no preparation: No preparation is done on any surface of the tooth for the luting of veneer.

Class 1—window preparation: This involves preparing the veneer short of the incisal edge and retaining the enamel over the incisal edge. The disadvantage here is the difficulty of hiding the margin.

Class 2—feather edge preparation: The preparation is taken or feathered to the incisal edge, with no reduction of the incisal edge length. The disadvantage of this preparation is that the margins can be subjected to shear forces in protrusion.

Class 3—bevel preparation: A bevel is carried over the incisal edge from buccal to palatal, with 1–2 mm of incisal reduction. A tooth preparation that incorporates incisal overlap is preferable, as the veneer is stronger and provides a positive seat during cementation. This preparation design has the advantage of simple tooth preparation, and the aesthetic characteristics are easier to fabricate with the ceramist, as it is possible to develop incisal translucency. The margin should not be in a position where it will be subjected to protrusive forces during excursive

**Figure 5.** *Classification of veneers based on tooth preparation.*

movements, therefore reducing the stress within the veneer while distributing the occlusal load over a wider surface area.

Class 4—overlapping preparation of incisal edge: The incisal edge is reduced with the preparation, then extended onto the palatal aspect. A positive seat is provided with this preparation, although there is a need to carefully evaluate the path of insertion to ensure that no undercuts are present.

Class 5—butt joint preparation: The butt joint preparation gives a 90-degree preparation all around the tooth that is to receive a veneer. The disadvantage is increased cutting of tooth structure.

Class 6—full veneer preparation: More or less like an anterior preparation for receiving a full veneer crown.

#### **3.2 Indirect porcelain veneers**

The indications, contraindications and advantages and disadvantages of indirect veneers are enumerated in **Tables 1** and **2**, respectively [8, 9].

#### **3.3 Clinical procedure**

#### *3.3.1 Labial preparation*

The preparation of the labial contour of anterior teeth must be done in three planes (3-plane reduction): incisal, middle third and cervical (**Figure 6**).

Careful depth reduction of the tooth is done to provide a minimum of 0.3 mm (feldspathic porcelain) or 0.6 mm (Empress, e max) preparation. The enamel thickness at the gingival third is 0.3–0.5 mm, up to 0.6–1 mm at the middle third and 1.0–2.1 mm at the incisal third.

The use of depth cutters or grooves and dimples has been recommended to control tooth preparation [9].

#### *3.3.2 Incisal edge reduction*

Four different preparation designs were possible (**Table 3**) (**Figure 7**) [9].

#### *3.3.3 Proximal reduction*

The proximal preparation can be done by stopping short of breaking the contact, or by preparing through the contact point.

#### **Table 1.**

*Indications and contraindications of indirect veneers.*

#### **Table 2.**

*Advantages and disadvantages of indirect veneers.*

#### *Aesthetic Smile Designing DOI: http://dx.doi.org/10.5772/intechopen.110465*

## **Figure 6.**

*Labial preparation.*

#### **Table 3.**

*Different preparation designs.*

• Preparations may extend further proximally with the presence of caries and existing restorations. Never should a margin lie on restoration or caries and should always lie on sound enamel [9].

#### *3.3.4 Cervical margin*

**Figure 7.** *Reduction according to type of veneer preparation.*

The prepared tooth then must be finished using finishing burs and abrasives and polished using pumice such that smooth surfaces are obtained [10].

#### *3.3.5 Impressions*

After the tooth prep is done, retraction cords are placed such that all the gingival margins are exposed. An accurate impression material such as polyvinyl siloxane, polyether or reversible hydrocolloid (agar) is used and a final impression is made.

Either a single-step impression or a two-step putty wash impression is made.

With advancement in technology, optical impressions are also being made. These impressions integrated with CAD CAM can instantaneously produce the required veneer [10].

#### *3.3.6 Temporisation*

The provisional restorations must be placed to improve interim aesthetics and decrease sensitivity. They also provide essential diagnostic information like veneer colour, shape, length and incisal edge configuration.

If it is a single-tooth veneer, the safest option is a light cured composite, which is used to directly build the tooth up. Central spot etching is done. No overhanging resin composite at the margins should be seen (Direct technique).

When provisionals for multiple teeth are needed, it is preferable to use a clear matrix made on a preop diagnostic cast. The teeth are spot etched, washed and dried. The facial and incisal areas in the clear matrix are filled with resin composite and the matrix is placed on the teeth and cured after removal of the excess. Instead of the composite, bis-acrylic temporization material (e.g. Luxatemp, DMG, Germany) can also be used (Indirect technique) [8].

#### *3.3.7 Try-in and luting*

After the veneer is obtained, the fit and shade are all evaluated in the try-in procedure and luting is performed. The teeth are treated with either the total-etch or self-etch protocol and the intaglio surface of the veneer is treated with 10% hydrofluoric acid. Resin cement is used to lute the veneer and the excess cement is removed and finishing and polishing the finish line [9].

#### **3.4 Indirect composite veneers**

#### Aka semi-direct veneers

The clinical technique is similar to that of indirect porcelain veneer. Instead of porcelain, the resin composite is used to create veneers extra orally and these are cured and fired/autoclaved to provide extra resistance to fracture. The finishing and polishing of the composite veneers are also done extra orally. Resin cement is used to lute these semidirect veneers after treating the tooth with self-etch or total-etch bonding protocol.

The advantages include better strength and fracture resistance, chair-side controlled contouring, single appointment completion and minor adjustments that can be done while carrying out the procedure.

The disadvantages include long chairside appointments and proper patient compliance and are technique sensitive.

#### *3.4.1 Failures of indirect veneers*

These are categorised as [8]:

#### 1.Mechanical

This includes (i) Fracture—poor positioning of the incisal margin, less incisal thickness and margin placed too sub-gingivally. (ii) Debonding—use of expired cement for luting and faulty veneer/tooth preparation.

#### 2.Biological

Biological failures include (i) post-operative sensitivity (ii) improper curing of cement, (iii) exposed margins, (iv) poor marginal adaptation, (v) margins at DEJ and (vi) marginal microleakage due to poor fit and extension.

#### 3.Aesthetic

Aesthetic complications include (i) improper shade selection and (ii) over contouring or improper margin placement in cases of gingival recession.

#### **3.5 Direct veneers**

A direct veneer is built up over the tooth surface by hand with composite material. They are indicated in cases of aesthetically compromised anterior teeth, when one desires a younger and better smile, in cases of discoloured teeth, closure of diastemas and space closures, fractured teeth, anatomically malformed teeth, patient is a bruxer and clencher (Indirect veneers are contraindicated in such patients) [8, 11].

Whereas in patients with unacceptable occlusion, actively erupting tooth, presence of periodontal disease, insufficient coronal tooth structure, enamel irregularities or deficiencies, and extremely dark and stained tooth (underlying discolouration visible through the veneers) direct veneers are contraindicated [8, 11].

Advantages and disadvantages

The advantages associated with these veneers are that it can be done in a single visit, the dentists have chair side control of tooth anatomy, it can be repaired, patient compliance is not compromised, cheaper than the other alternative and there is minimal irreversible loss of tooth structure as the preparation is almost next to nil [8, 11].

On the contrary, they tend to discolour, there is increased chair side time, physical limitations of the material, they wear out more quickly, often require repair and have higher chances of replacement and marginal staining [8, 11].

#### *3.5.1 Diagnostic considerations*

Direct veneers can be done only when there is adequate amount of enamel present, there is tooth discolouration, in cases of orthodontic problems, in patients with habits like tobacco chewing or smoking, edge-to-edge occlusion, parafunctional habits and when one needs to meet patient's expectations immediately [9].

#### *3.5.2 Treatment planning and shade selection*

Two sets of models are made so that one can be used to study the patients' teeth and occlusion while another is used for a trial build-up (also known as an aesthetic mock up). A putty index is taken from it to replicate the mock-up [10].

Pre-operative photographs in natural lighting and monochrome must be taken to correctly evaluate the shade of the teeth. Shade tabs or colourimeters can also be used to determine the correct shade of the teeth. Another technique to achieve complex shades is the application of composite resin on non-bonded tooth surfaces and curing of the composite resin [8]. The first shade to be matched is for the dentin layer, followed by the shade for the enamel in the cervical and incisal areas [12].

#### *3.5.3 Clinical steps*

After shade matching, an intra-enamel tooth preparation should be done to a minimum depth of 1/4th to 3/4th thickness of enamel (depending on the severity of the case). Following this, the teeth are etched with 35% orthophosphoric acid, washed, dried and checked for frosty appearance. Next, the bonding agent is applied, air-dried and polymerised using light cure unit. After this, putty index is placed and placement of composite resin in layering technique is done to ensure shade matching. In case of dark discoloured teeth, an opaquer is used to mask the effect following which a dentin layer and enamel layer (cervical and incisal respectively) being applied and light cured. Finishing and polishing done 10 minutes after complete polymerisation are achieved. Burs, discs and wheels are used to reduce excess contours and final finishing and polishing are done using diamond discs and cups with polishing paste [9].

#### *3.5.4 Failures of direct veneers*

Composite veneers show around 60–70% of success rates in clinical studies. However, failures are seen to occur 2 to 5 years after placement what so ever the protocol or material is used.

Periodontal involvement: Due to the finish lines located near gingival margin and the presence of substances such as excess composite or bonding agents in the gingival crevices, which can act as irritants, gingival inflammation can occur.

Marginal breakdown: White lines may be seen as a result of finishing process. The composite tends to tear at the margins due to the effect of polymerisation shrinkage and the heat and friction produced during the finishing and polishing of the newly placed composite.

Occlusal-related chipping: This is seen especially in patients with parafunctional habits. Hence, the length and contouring of the veneer should be decided and perfected. Also, the occlusal table can be widened by adding extra material on the cuspid tip to resist shear forces.

Chipping at contact area: Seen due to occlusal trauma or fatigue caused by cyclic fatigue. A chamfer or rounded shoulder margin should be placed to avoid such chipping.

Layer separation: Occurs when composite is inadequately bonded to the tooth and other layers. Layering of composite under a completely sterile environment and carrying out proper polymerisation of each layer to prevent the presence of unpolymerized resin [9].

#### *3.5.5 Strategies to repair failed direct veneers*

Minor marginal breakdown can be treated with discing. Discing removes the damaged area and exposes the sound restoration underneath.

The repair of fractured composite such that new material is layered over existing composite should never be attempted. If a restoration needs repair, the old composite should be removed completely and the restoration must be repeated.

When a properly placed composite in a stress-bearing area fractures due to overloading stress, a better stress-bearing and stronger material should be used to restore the tooth instead of repeating the composite restoration [9].

#### **4. Recent advances**

#### **4.1 Lumineers**

Lumineers are made from a special patented Cerinate porcelain that is very strong but much thinner than traditional laboratory-fabricated veneers. The thickness is comparable to contact lenses [13]. Lumineers are a reversible procedure and it hardly requires removal of tooth structure. They will bond directly to the tooth and the longevity is up to 20 years.

Componeer (Coltene, Altstten, Switzerland) prefabricated veneers are thin composite resin shells (0.3 mm cervically and 0.6–1.0 mm to the incisal edge). These prefabricated veneers are made of a pre-polymerised hybrid composite resin and Synergy D6 (Coltene, Altstten, Switzerland) [14].

#### **4.2 Digital smile designing (DSD)**

With the new era of digitalization, use of softwares and computers allow for a repeatable and reproducible functional and aesthetic result. Components of DSD include a computer, DSD software, digital single-lens reflex (DSLR) camera or smartphone camera, intra-oral scanner, a printer and CAD/CAM system [15].

#### **4.3 Photography and videography**

Good quality photographs are a must as it forms the baseline to evaluate the changes as well as plan the treatment. It helps to form the facial and gingival reference lines such as the commissural lines, lip line and inter-pupillary line. The photographs and videographs should be taken accordingly (**Tables 4** and **5**) [15–17].

These images are uploaded in software that helps carry out the DSD. Various softwares are available depending on factors such as the dentist's ease of use, digital workflow, cost, time effectiveness and compatibility with other digital tools and systems, for example, Smile designer Pro, Tasty Tech ltd. Toronto, Ontario, Canada; Microsoft PowerPoint, Microsoft Office, Redmond, Washington, USA; Keynote, iWork, Apple, Cupertino, California, USA.

Given the history of humans and their inspiration by principles of nature, the digital tool just like a manual tool performs facial analysis [18]. The horizontal (inter-pupillary and inter-commissural lines) and vertical references (facial midline through the glabella, nose and the chin) are marked and drawn against each other to calculate the facial symmetry. The software then places the wide smile photograph of the patient behind these reference lines to measure the vertical midline

**Table 4.** *Photographs.*

#### **Table 5.**

*Videographs.*

and horizontal plane for comparative evaluation between the teeth and face. Next, the dento-gingival analysis is done. Gingival display and smile curve is established and dental contouring is done based on the curvature of the lower lip and anteroposterior curvature of the teeth. Reference lines such as horizontal canine to canine tip, horizontal lines through incisal edges, vertical midline and gingival zenith are drawn to match the facial analysis. The dental length-to-width ratio is established by incorporating any one of the dental proportions such as the golden proportion, Pound's theory, recurring aesthetic dental proportion and Dentogenic theory or Visagism (using temperament in concept of smile design, introduced by Braulio Paolucci). All the above measurements are then transferred to a 3D cast. Wax-up is then done and reflected onto the cast. The software then uses tools to make necessary changes and the final image is presented to the patient, this final image can also be altered based on the patient's aesthetic needs and requirements. A 3D printer is used to process the digital wax-up, silicone index can be prepared out of the model and can be processed to create a provisional restoration. Mock-ups and alterations can be done on it. The final changes can be made and a scanner is used to feed it to the CAD/CAM machine [15–17]. The final approved 3D image of the preparation is obtained and final prosthesis is designed by the machine, this is called computeraided designing. Appropriate size of the ceramic is chosen and the milling machine produces the veneers in accordance with the details fed into the computer [19]. An alternative method would be computer-aided designing/additive manufacturing using 3D printing to overcome the wastage of the material.

Various veneer materials are available and used by the CAD/CAM system such as feldspathic ceramics, mica-based ceramics, leucite-reinforced ceramics, lithium disilicate reinforced ceramics, glass infiltrated alumina and zirconia ceramics, polycrystalline alumina and zirconia, which includes yttria partially stabilised tetragonal zirconia polycrystals, magnesium partially stabilised zirconia and ceria stabilised zirconia/alumina nanocomposite. In 3D printing, the options available are light-cured resin, methacrylate-based resin, composites, hybrid composite resin, experimental PMMA-based nanocomposite, polymers and ceramic-filled hybrid resins such as experimental lithium disilicate-based ceramic-filled photosensitive resin [19, 20].

#### **Advantages**

Improved diagnosis and treatment planning. Visualisation of treatment outcome. Patients' involvement and satisfaction. Better communication amongst dentists as well as the dentist and the patient. High-quality pre- and post-treatment evaluation [15–17]. **Limitations** Dependency on accurate photographs and videos. Expensive.

Need to have updated knowledge and skill to work with technology [15–17].

## **5. Conclusion**

Creating a smile requires thorough knowledge and skill to replicate the natural smile. One needs to consider the components of smile designing, which includes the tooth as well as the gingival counterparts. Consideration of various proportions to achieve the shape, symmetry, function and aesthetic is required. With availability of tooth-coloured materials, achieving a natural smile is now possible. Composite or ceramic veneers help achieve maximum beautification with minimal preparation. Moreover, popularisation of software tools and CAD/CAM systems will help achieve maximum precision and patient satisfaction.

#### **Author details**

Monisha P. Khatri1 \*, Shreya Kishore2 and Srujana Hemmanur1

1 Department of Conservative Dentistry and Endodontics, SRM Institute of Science and Technology, SRM Dental College, Ramapuram, Chennai, India

2 Department of Orthodontics, SRM Institute of Science and Technology, SRM Dental College, Ramapuram, Chennai, India

\*Address all correspondence to<EMAIL_ADDRESS>
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

[1] Bhuvaneshwaran M. Principles of smile design. Journal of Conservative Denstistry. 2010;**13**(4):225-232

[2] Nigam M et al. Esthetic design. Journal of Orofacial Research. 2015;**5**(4):130-133

[3] Calamia JR, Wolff MS. The components of smile design: New York University smile evaluation form revisited, update 2015. Dental Clinics. 1 Jul 2015;**59**(3):529-546

[4] Sabri R. The eight components of balanced smile. JCO. 2005;**36**(3):155-167

[5] Chakroborty G, Pal TK, Chakroborty A. A study on gingival component of smile. Journal of the International Clinical Dental Research Organization. 2015;**7**(2):111-115

[6] Calamia JR, Levine JB, Lipp M, Cisneros G, Wolff MS. Smile design and treatment planning with the help of a comprehensive esthetic evaluation form. Dental Clinics. 1 Apr 2011;**55**(2):187-209

[7] Lo ML. Book review: Mosby's dental dictionary. British Dental Journal. 2014;**217**(4):168

[8] Albers HF. Tooth colored restorations. In: Principle and Techniques. 9th ed. Hamilton. London: BC Decker Inc; 2002. p. 97

[9] Goldstein RE, Chu SJ, Lee EA. Stappert CF. In: Ronald E, editor. Goldstein's Esthetics in Dentistry. USA: John Wiley & Sons; 2018

[10] Tylman SD, Malone WF. Tylman's Theory and Practice of Fixed Prosthodontics. 7th ed. St. Louis: Mosby; 1978. pp. 96-134

[11] Robertson T, Heymann HO, Swift EJ Jr. Sturdevant's Art and Science of Operative Dentistry. Philadelphia, PA, USA: Elsevier Health Sciences; 2006

[12] Fahl N, Ritter AV. Composite veneers: The direct–indirect technique revisited. Journal of Esthetic and Restorative Dentistry. 2021;**33**:7-19. DOI: 10.1111/ jerd.12696

[13] Zlatanovska K, Dimova C, Zarkova-Atanasova J. Minimally invasive aesthetic solutions - porcelain veneers and lumineers. DDF. 2017;**376**:111-120. DOI: 10.4028/www.scientific.net/ ddf.376.111

[14] Gomes G, Perdigão J. Prefabricated composite resin veneers–A clinical review. Journal of Esthetic and Restorative Dentistry. 2014;**26**(5):302- 313. DOI: 10.1111/jerd.12114

[15] Jafri Z, Ahmad N, Sawai M, Sultan N, Bhardwaj A. Digital smile design-an innovative tool in aesthetic dentistry. Journal of Oral Biology and Craniofacial Research. 2020;**10**(2):194-198

[16] Thomas PA, Krishnamoorthi D, Mohan J, Raju R, Rajajayam S, Venkatesan S. Digital smile design. Journal of Pharmacy and Bioallied Sciences. 2022;**14**(5):43

[17] Cervino G, Fiorillo L, Arzukanyan AV, Spagnuolo G, Cicciù M. Dental restorative digital workflow: Digital smile design from aesthetic to function. Dentistry Journal. 2019;**7**(2):30

[18] Basheer N, Madhubala MM, Mahalaxmi S. Future perspectives of biomimetics in restorative dentistry. Journal of Pharmaceutical Research International. 2020;**32**(25):19-28

[19] Liu PR, Isenberg BP, Leinfelder KF. Evaluating CAD-CAM generated ceramic veneers. Journal of the American Dental Association. 1993;**124**(4):59-63

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Section 2


3.2.2. Demonstrating the Way to Use Index Components

The way to use the components of the index is illustrated below, in a specific example of a project that combines BIM in green building. The examination of the integration between the two is performed using three tables: SNA results table for the actual implementation of BIM in green building (Table 1), SNA results table for optimal implementation of BIM in green building, according to standard assumptions (Table 2), and table of findings of the Green BIM Index (Table 3). This project relates to a detailed design stage of a cafeteria. Although the standard assumption in the given project refers to 12 required stakeholders, in practice, two of them did not participate in the sample (the tenant and the landscape architect).

**Table 1.** SNA results for the actual implementation of BIM in green building.

**Table 2.** SNA results for optimal implementation of BIM in green building.

**Table 3.** Green BIM Index findings.

The assumption for a BIM manager is that he/she sends information to everyone daily, receives information from key participants on a daily basis, receives information from the secondary to them on a weekly basis while receiving from other participants on a monthly basis. In the example, the BIM manager did send information as required but did not receive a standard response (some sent on a weekly basis, and some did not send at all). The assumption results in a weighted degree of 273 compared to 228 in practice, resulting in an index finding of 0.84 (X1).

In addition, according to the standard, all involved, professionals and tenants alike, should be connected, directly or indirectly, to a BIM-based social network. This is reflected in 11 optimal connections versus nine actual connections, resulting in an index finding of 0.8 (X2).

Besides, the standard assumption is that there is no interaction but through a BIM-based network and with a BIM manager or agents. This is shown in the result of 10 optimal connections of professionals compared to nine of their actual connections and in an index finding of 0.9 (X3). This is in addition to one optimal connection of a tenant representative compared to 0 connections of an actual tenant representative and to an index finding of 0 as a result (X4).

The Green BIM Index score in relation to the BIM application at the detailed design stage in the green building project is 0.64 (X5). This index can be used as a means of improving capabilities in additional stages. Figure 1 graphically shows the performance metrics at the given stage.

**Figure 1.** Graphical display of the Green BIM Index components.


*5.1. Candidate Gene Studies*

Literature on the genetics of FMD is scarce and, when available, studies are generally underpowered to assess the role of the tested genes. The main reason is the lack of large pedigrees to perform linkage analyses or large cohorts of well-characterized FMD patients for association studies. Variants in genes belonging to pathways related to the extracellular matrix of the arterial wall failed to show significant or even promising associations with FMD. Single Nucleotide Polymorphisms (SNPs) in the elastin gene (*ELN*), which harbours causative mutations for supravalvular aortic stenosis in Williams–Beuren syndrome (OMIM reference: #194050) (Perdu & Jeunemaitre, Unpublished data), as well as in the alpha1-antitrypsin gene (*AAT*) [42], were distributed evenly in patients with FMD and healthy controls or patients with essential hypertension. The modest sample size (*N* cases = 161) and lack of comprehensive coverage of the genes of interest, including regulatory regions, may partially explain these negative findings. Screening for causative mutations in the actin α-2 gene (*ACTA2*), involved in rare cases of aortic aneurysms was also negative [43]. Finally, as indicated above, screening for mutations involved in rare vascular syndromes such as Marfan, Loeys-Dietz and vascular Ehlers-Danlos Syndrome, in the TGFβ signalling pathway and/or extracellular matrix components (e.g., fibrillin and collagen genes) was disappointing [26,37]. Fortunately, the development of Next Generation Sequencing (NGS) opened the possibility to conduct hypothesis free experiments, such as exome sequencing, to explore families.


**3. Results**

156 The Dynamical Processes of Biodiversity – Case Studies of Evolution and Spatial Distribution

possibility for vegetation data is to regress similarity of units regarding species composition against their geographical separation (Nekola and White, 1999; Steinitz et al., 2006). To test for the influence of different vegetation types on patterns of compositional similarity data was divided into subsets. As the plots can be assigned to 2 geographically distinct regions, the distance decay of different vegetation types and subsets based on other categorical variables

The similarity values of the subsets are compared with an ANOVA-like function (mrpp[vegan]), (Oksanen et al., 2007)) and tested for significant differences using a permutation procedure (diffmean[simba]). Normal tests and ANOVA might fail here

The Multiple Response Permutation Procedure (mrpp) allows testing whether there is significant difference between two or more groups of sampling units. The method is insofar similar to anova, in that it compares dissimilarities within and among groups. If two groups of sampling units are really different (e.g. in their species composition), then average withingroup compositional dissimilarities ought to be less than the average of the dissimilarities between two random collections of sampling units drawn from the entire population. The mrpp statistic delta gives the overall weighted mean of within-group means of the pairwise dissimilarities among sampling units. The mrpp[vegan] algorithm first computes all pairwise distances in the entire dataset, then calculates delta. Then the sampling units and their associated pairwise distances are permuted, and delta is recalculated based on the permuted data. The last steps are repeated N times. N defaults to 1000 which provides a possible significance-level of p<0.001 as significance is tested against the distribution of the

After testing for significant differences between subsets, the differences in mean similarity are tested with a permutation procedure (diffmean[simba]). The difference in mean similarity between two sets is calculated. The two sets are joints together and two random sets the same size as the original sets are selected and their difference in mean is calculated. Then the sampling units and their associated pairwise distances are permuted, and the difference in mean is recalculated based on the permuted data. The last steps are repeated N times. N defaults to 1000 which provides a possible significance-level of p<0.001 as

To answer the question if distance decay is significantly different between the various evaluated subsets of the data, the slopes of the distance decay relationship have been calculated for the three subsets and compared. A permutation procedure following Nekola & White (1999) has been implemented as an R function (diffslope[simba]) to test for significance. For each subset compositional similarity between plots is regressed against their geographical separation. Before calculating the difference in slope between two subsets the values of compositional similarity are rescaled to a common mean. So testing the difference in slope of the distance decay relationship is independent of differences in the mean (Nekola & White, 1999; Steinitz et al., 2006). Linear regression is carried out on both of the subsets, and the difference in slope is calculated and stored. Then the variable pairs (geographical separation, compositional similarity) are randomly reassigned to the two data-subsets. Regression is calculated for each of the random subsets and the difference in slope is obtained again. The last steps are repeated 1000 times. Finally the difference between the observed slopes is compared to the differences based on random reassignment. Number of times when randomization are being produced differences in slope which is higher than the original data are summed up and

(fragmentation, slope, disturbance, etc.) is compared between the two regions.

because the similarities are not independent from each other.

significance is tested against the distribution of the permuted values.

divided by the number of permutations to get a p-value.

permuted deltas.


Meet the editor

Dr. Aleksey Kuznetsov pursued his Ph.D. in Physical Chemistry at the Department of Chemistry and Biochemistry, Utah State University, and graduated after three years of doctorate studies with a specialization in Computational/Theoretical Chemistry. He has been working in various subareas of this field of research since 2000. After several postdoctoral and visiting professor positions in Germany, the United States, and Brazil, Dr. Kuznetsov

obtained a permanent faculty position at the Department of Chemistry, Universidad Técnica Federico Santa Maria, Santiago, Chile. He has been working there since 2019, focusing his research on the computational design of various complexes of porphyrins, including core-modified porphyrins, with nanoparticles, fullerenes, and graphenes, along with studies of transition metal complexes, organic compounds with pharmacological applications, and more.

Contents

**Section 1**

**Section 2**

**Section 3**

**Section 4**

*by Abdul Aziz Ali*

*by Nana Derkyi*

*by Aleksey E. Kuznetsov*

Antitrypanosomal Agents

*by Seham A. Ibrahim and Hala F. Rizk*

*by Brahim El Ibrahimi and Lei Guo*

**Preface XI**

Introduction **1**

**Chapter 1 3**

Thiazoles and Their Derivatives: Synthesis and Applications **11**

**Chapter 2 13**

**Chapter 3 33**

Triazoles: Synthesis and Applications **63**

**Chapter 4 65**

Miscellaneous Applications of Azoles **83**

**Chapter 5 85**

**Chapter 6 113**

Azole-Based Compounds as Corrosion Inhibitors for Metallic Materials

Azoles for Renewable Energy Development and Wood Treatment

*by Anna Kryshchyshyn, Danylo Kaminskyy, Philippe Grellier and Roman Lesyk*

Introductory Chapter: Azoles, Their Importance, and Applications

Synthesis and Biological Evaluation of Thiazole Derivatives

Thiazolidinone-Related Heterocyclic Compounds as Potential

1,2,3-Triazoles: Synthesis and Biological Application

## Contents

Preface

Azoles represent a broad, interesting, and promising class of five-membered heterocyclic aromatic compounds containing from one up to five nitrogen atom(s), which can also contain at least one sulfur or oxygen atom as a part of their conjugated ring (N,S and N,O subclasses of azoles, respectively). The parent azole compounds, as exemplified by imidazole, pyrazole, 1,2,3-triazole, tetrazole, and pentazole, are aromatic structures with two double bonds. Various successively reduced analogs, such as azolines and azolidines, with just one double bond, have been synthesized.

Only one lone pair of electrons from each heteroatom in the azole ring participates in the aromatic bonding. The numbering of ring atoms in azoles starts with the heteroatom that does not participate in the double bond and proceeds towards the other heteroatom. Imidazole, which contains two N atoms, and other five-membered aromatic heterocyclic compounds with two nitrogens (e.g., pyrazole) are extremely common in nature and form the core of many biomolecules, for instance, histidine,

Azoles have always been considered suitable scaffolding for the design of various novel therapeutic agents. Various oxygen-containing azoles, as exemplified by oxadiazoles, oxazoles, and isoxazoles, have been thoroughly studied for their diversified biological activities. Widely used as potent antifungal agents due to their valuable properties like a broad spectrum of action, chemical stability, and oral bioavailability, various azole derivatives have also demonstrated many other promising biological properties including antidiabetic, immunosuppressant,

This book includes four sections. The first section contains an introductory chapter written by the editor and explains the importance and applications of Azoles. The second section, "Thiazoles and Their Derivatives: Synthesis and Applications," is composed of two chapters. Chapter 2, "Synthesis and Biological Evaluation of Thiazole Derivatives," presents the several types of thiazole-based heterocyclic scaffolds (monocyclic or bicyclic systems), their synthesis, studies of their biological activities, and the modifications of thiazole-based compounds to generate new molecules with potent antitumor, antioxidant, and antimicrobial activities. Chapter 3, "Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents," describes the development of 4-thiazolidinone and thiazole derivatives with heterocyclic fragments, which exhibit good inhibition of trypanosome growth and might be potential candidates for the development of

The third section, "Triazoles: Synthesis and Applications," contains one chapter. Chapter 4, "1,2,3-Triazoles: Synthesis and Biological Application," considers numerous synthetic approaches for the synthesis of 1,2,3-triazoles, especially the popular click chemistry approach, and discusses several biological activities of

or parts of purine nucleobases.

anti-inflammatory, and anticancer activities.

new drugs against trypanosomiasis.

these promising heterocycles.


**8. Pulmonary hypertension**

Pulmonary hypertension in CDH is persistent, recalcitrant and difficult to treat. The management is compromised by the scarcity of good quality research and evidence. The presence of PPH is the most significant predictor and cause of morbidity and mortality, as well as of the need for ECMO [83]. Pulmonary hypertension in CDH is characterized by the hypoplasia of pulmonary vascular bed, remodeling of pulmonary vasculature, and an altered vasoreactivity of the pulmonary vessels. The pulmonary vasculature remodeling is characterized by the medial and adventitial thickening of the midsized and large vessels' walls and by the neomuscularisation of small capillaries. The vascular remodeling is evidenced to begin at as early as the 19th weeks of gestation in human lungs of CDH patients, and is associated with an earlier maturation of the pulmonary vasculature [167]. The pulmonary hypertension in CDH has both fixed and variable components. Reduced pulmonary vascular cross sectional area and the vascular remodeling contribute to the fixed component

of PPH. The reactive component of PPH is balanced by the circulating vasoconstrictor and vasodilator agents and defines the response to vasodilator treatment. Increased expression of the vasoconstrictive factors (endothelin A and B receptors, endothelin converting enzyme-1) and a decreased expression of the vasodilators (prostaglandin-I2 receptor) have been reported in CDH [168]. The reports about the concentration of endothelial nitric oxide (eNOS) in CDH patients are conflicting [169–172]. An extensive review of the factors and pathways involved in the vascular remodeling in CDH has been published [173].

The utility and selection of pulmonary vasodilator agents for the treatment of PPH often change, as the underlying pathophysiology evolves during the days and weeks following the birth. The management strategies need to be adjusted as the pulmonary vascular abnormalities progress from acute to subacute and finally to the chronic stage. A poor response to the vasodilator therapies during acute phase is attributed to the left ventricular (LV) hypoplasia and dysfunction, in association with pulmonary venous hypertension [174]. In some CDH patients, there may be a "honeymoon" period displaying good oxygenation during the 1st few hours of life. Ratio of the pulmonary arterial to systemic arterial pressure (P/S ratio) is used to evaluate the degree of PPH. A P/S ratio <2/3 of systemic systolic pressures is considered as normal or mild; whereas, that of ≥2/3 of systemic pressure denotes moderate; and if > systemic pressure, severe PPH [175]. Important parameters to check in the neonatal echocardiography are the direction and velocity of flow at ductal and foramen ovale shunts, flattening or left deviation of the interventricular septum, and tricuspid regurgitation jet velocity. Functional evaluation of the right and left ventricles is the key that guides the appropriate pulmonary vasodilator therapy. Lung recruitment with adequate positive end-expiratory (PEEP) or mean airway pressure and/or with surfactant to achieve an expansion up to 8- to 9-ribs during inspiration is the goal. Overriding right-to-left shunt by increasing systemic vascular resistance is not recommended. Severe PPH with right to left shunt at the atrial level necessitates the emptying of right ventricle, which is accomplished by maintaining the patency and reopening of ductus arteriosus with prostaglandin E1 if needed [176, 177]. Such cases may respond favorably to the inhaled nitric oxide therapy (iNO). LV dysfunction is associated with left-to-right atrial shunting and suggests the presence of pulmonary venous hypertension, which is associated with poor response to pulmonary vasodilator therapy [178]. Milrinone is recommended in patients with LV dysfunction due to its lusitropic, inotropic and pulmonary vasodilator properties [174]. A retrospective study reported improved cardiac function and reduced right ventricular pressure with milrinone in PPH associated with CDH [179]. As there is a potential risk of systemic hypotension, the avoidance of loading dose or priming the system with normal saline bolus were suggested by the researchers in some case series studies [180, 181]. Prospective RCTs of milrinone in CDH complicated by PPH are lacking and are warranted [182].

The Neonatal Inhaled Nitric Oxide Study (NINOS), which included 53 infants with CDH showed no difference in the combined primary outcome of death or ECMO utilization between the iNO-treated patients and controls [183]. In fact, ECMO utilization was higher in the iNO-treated group (80% vs 54% control, p = 0.043), indicating an adverse effect of iNO if used early in the course of PPH associated with CDH [183]. The ventilation approach, choice of the ventilator and the OI at enrollment in this study were different from the current practices. Their result further supported the important role of left ventricular dysfunction in PPH in CDH cases [178]. The use of iNO was associated with significantly higher mortality in CDHSG registry cases as well [184]. However, despite a lack of evidence, inhaled nitric oxide is commonly used in the management of PPH in CDH [179, 184].

**133**

**10. Surgery**

*Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists*

reversibility of PPHN is not possible with the current knowledge.

**9. Extracorporeal membrane oxygenation**

ered as a therapeutic option in those centers that offer it.

require a patch (76.9% vs 96.5%) [10].

**11. Follow-up and outcomes**

In the nonresponders to iNO, or in the resource poor settings where iNO is often unavailable, sildenafil is a feasible option. Trials to evaluate the effect of sildenafil in newborns with persistent pulmonary hypertension of the newborn (PPHN) have been conducted. A meta analysis showed that sildenafil reduces mortality and improves oxygenation in PPHN [185]. However, there are limited data on the use of sildenafil in CDH patients. In retrospective studies, both oral and IV formulations of sildenafil were shown to improve oxygenation in CDH patients [186, 187], although IV sildenafil resulted in an increased need for inotropic support [188]. The Congenital Diaphragmatic hernia Nitric Oxide versus Sildenafil (CoDiNOS) trial is the first prospective RCT that has been recently proposed [189]. Other drugs under consideration are epoprostenol, treprostinil, inhaled alprostadil and bosentan. At this time, there is insufficiant evidence in regards to their efficacy or safety for use in PPHN [190–192]. It is reasonable to comment that an accurate prediction of the

Congenital diaphragmatic hernia is the most common non-cardiac indication for extracorporeal membrane oxygenation in the neonates, even though the benefits of the intervention in terms of mortality in CDH are questionable. A retrospective study of the extracorporeal life support organization (ECLS) registry data revealed the overall survival of 48.1% in term neonates representing a 13.8% reduction in survival of neonates with CDH who were treated with ECMO [193]. This result probably represents the fact that more serious CDH cases were subjected to ECMO [194]. CDHSG registry data, on the other hand, have documented an improved survival in the most severely affected CDH patients with ECMO [195]. The recently published VICI trial [136] failed to demonstrate any difference in CDH outcomes between ECLS and non-ECLS centers, further questioning the role of ECMO in CDH. The indication and utility of ECMO in CDH is still evolving, as is the timing of surgery. It should be discussed during prenatal counselling and may be consid-

The reduction of herniated abdominal contents does not improve PPH in CDH

A multidisciplinary approach is needed for the comprehensive long term follow up of the neonates with CDH. A myriad of significant morbidities may affect these neonates, which includes respiratory disorders (chronic lung disease, pulmonary

and thus the outcome remains largely unaffected. A systematic review on the subject has not favored either early or late surgery [154]. The recommended physiologic criteria for preparedness for surgery are not supported by evidence [81, 143]. However, It is possible that early repair on ECMO may improve outcome [154]. In stable patients, CDH repair is usually done between 48–72 h after birth. Recurrence rate is significantly lower in open repair [154]. Polytetrafluoroethylene (PTFE) is the most durable patch repair material. Even though the survival in patients requiring patch repair has significantly improved, it is still lower than those who do not

*DOI: http://dx.doi.org/10.5772/intechopen.94839*

#### *Congenital Diaphragmatic Hernia: A Major Challenge for Neonatologists DOI: http://dx.doi.org/10.5772/intechopen.94839*

In the nonresponders to iNO, or in the resource poor settings where iNO is often unavailable, sildenafil is a feasible option. Trials to evaluate the effect of sildenafil in newborns with persistent pulmonary hypertension of the newborn (PPHN) have been conducted. A meta analysis showed that sildenafil reduces mortality and improves oxygenation in PPHN [185]. However, there are limited data on the use of sildenafil in CDH patients. In retrospective studies, both oral and IV formulations of sildenafil were shown to improve oxygenation in CDH patients [186, 187], although IV sildenafil resulted in an increased need for inotropic support [188]. The Congenital Diaphragmatic hernia Nitric Oxide versus Sildenafil (CoDiNOS) trial is the first prospective RCT that has been recently proposed [189]. Other drugs under consideration are epoprostenol, treprostinil, inhaled alprostadil and bosentan. At this time, there is insufficiant evidence in regards to their efficacy or safety for use in PPHN [190–192]. It is reasonable to comment that an accurate prediction of the reversibility of PPHN is not possible with the current knowledge.


**9. Embed third-party resources to increase serious game interactivity**

What do you do if you want to increase online learner engagement and immersion, but you do not have the time or resources to develop additional content?. You can enhance the game by embedding third-party resources, you can have add ons for your serious game without having to create everything in-house. Include a link to a helpful tutorial that walks online learners through a task, or embed a YouTube video that explores a topic at length. You can even create printer-friendly eLearning courses by integrating PDF files and other downloadable documents that online learners can access via the serious game.


*Article* **RANS Prediction of Wave-Induced Ship Motions, and Steady Wave Forces and Moments in Regular Waves**

**Qingze Gao 1,2, Lifei Song 1,2,\* and Jianxi Yao 1,2,\***

**Abstract:** The wave-induced motions, and steady wave forces and moments for the oil tanker KVLCC2 in regular head and oblique waves are numerically predicted by using the expanded RANS solver based on OpenFOAM. New modules of wave boundary condition are programed into OpenFOAM for this purpose. In the present consideration, the steady wave forces and moments include not only the contribution of hydrodynamic effects but also the contribution of the inertial effects due to wave-induced ship motions. The computed results show that the contribution of the inertial effects due to heave and pitch in head waves is non-negligible when wave-induced motions are of large amplitude, for example, in long waves. The influence of wave amplitude on added resistance in head waves is also analyzed. The dimensionless added resistance becomes smaller with the increasing wave amplitude, indicating that added resistance is not proportional to the square of wave amplitude. However, wave amplitude seems not to affect the heave and pitch RAOs significantly. The steady wave surge force, sway force and yaw moment for the KVLCC2 with zero speed in oblique waves are computed as well. The present RANS results are compared with available experimental data, and very good agreements are found between them.

**Keywords:** wave-induced ship motions; steady wave force and moment; inertia effects; RANS; OpenFOAM