**2. Osteotomy and corticotomy**

The DO procedure begins with the transverse section at a diaphyseal or metaphyseal level of the long bone to be elongated. Ilizarov described three methods to create fractures, including osteotomy, corticotomy, and osteoclasis. The osteogenic potential of the osteotomy or corticotomy depends on three main factors: the localization in bone, the type of technique used, and the latency period subsequently applied [6, 7].

Regarding the localization, some researchers in the past referred that the bone lengthening should be performed in the middle of the diaphysis of the long bone, and when necessary elongation was obtained, a bone graft from the ilium crest could be applied on the distraction focus to promote its consolidation. Later, Ilizarov recognized the metaphysis as the ideal site for the osteotomy, due to its massive trabecular bone area, rich in collateral vascularization, and higher potential for fracture recovery. Other researchers compared the regenerated bone quality at the diaphysis and metaphysis after DO, while using different latency periods. In the metaphysis, latency periods of 0 and 7 days allowed a greater osteogenesis and a faster remodeling and consolidation, when compared to the diaphysis elongation. A latency period of 14–21 days was associated with a premature consolidation in both regions. Bone mineralization of the newly formed tissue was faster at the metaphysis than at the diaphysis. Curiously, when there was no latency period, the distraction was successful and the consolidation faster. The latency of 7 days did not reveal the risk of premature consolidation; however, the consolidation and bone formation were slower than where there was no latency period. *Post mortem* torsion and bending test revealed that the bone tissue elongated on the metaphysis was tougher and more resistant. Histologically, the osteogenesis is observed to be based on intra-membranous ossification and, when a longer latency period is performed, increased proliferation of cartilaginous tissue at the osteotomy focus is detected, resulting in an endochondral ossification which may end up resulting in a slower process. The same study revealed that the metaphysis has more viable characteristics for the DO than the diaphysis [8].

Kojimoto and collaborators showed, in rabbits, the importance of the periosteum, referring that when it is removed, a bone callus is not formed and the bone lengthening can fail [9]. Ilizarov considered the preservation of the periosteum, and the medulla vascularization as mandatory to obtain better results on a DO [7, 10, 11]. Ilizarov developed the subperiostal osteotomy technique in which the anterior, medial, and lateral portions of the cortex are sectioned, and the posterior side is the manually fractured, thus preserving the medullar vasculature. Although Ilizarov defends the importance of the medullar vasculature, other authors question its importance [9, 12, 13].

#### **3. Segment stabilization**

The distraction is performed using an external fixation system, and this can be a circular Ilizarov or and longitudinal monoplane unilateral frame [3]. It is imperative to keep an adequate stabilization of the fracture, its alignment, and osteodistraction [11, 14].

The external fixator frame rigidity must prevent unnecessary micro-movements at the osteotomy site, but, at the same time, it should be compliant to allow bone

**95**

*Distraction Osteogenesis: Biological Principles and Its Application in Companion Animals*

tissue inducting micro-movements along the axial axis [14–16]. A stable external fixator with less stiffness decreases the time to achieve bone consolidation. Moreover, the time of consolidation with low mechanical score (less rigid) is

Kusec and colleagues compared the bone tissue formed by DO using a unilateral distractor and an Ilizarov distractor, in a population of 15 German Shepherd dogs. No histological or radiographic differences were found on the newly formed bone tissue. The regeneration progressed in centripetally from the cortex and the intramembranous ossification was predominant at the medullar portion of the distraction focus [17]. The Ilizarov fixator, comparing to Wagner, Orthofix, and Oxford unilateral frames, is also flexible with a consistent stiffness to bending moments in anteroposterior and lateral planes. Moreover, the Ilizarov fixator is more resistant to axial compression with increasing load and is more flexible in the axial direction

During bone lengthening, the distraction moment where the screws are tightened or loosened in the external device frame may create instability on the distraction focus and therefore adversely affect the procedure. The use of new compounds, such as highly dense plastics, interconnected with metal alloys, helps to prevent

The latency period begins immediately after the osteotomy and extends to the beginning of the distraction. This may be characterized as a "rest" period after the corticotomy to allow a tissue response to the iatrogenic trauma. This response includes a proliferation of fibroblast and the induction of a state of periosteal reactivity, phenomena which occur at the beginning of a fracture regeneration [3]. The latency period allows an organization of the hematoma and the fibrous tissue matrix, which will serve as a mold to the osteoblast proliferation, that on the first 24 hours produce osteoid at the bone surfaces. This period also allows a periosteal

In rabbits, the importance of the latency period was demonstrated in a tibial DO. A 7-day latency period allowed a greater regeneration at the distraction focus and increased vasculature, in opposition to a DO without latency period characterized by a fibrous tissue formation [21]. Other studies showed that the existence of a latency period allows the formation of cartilaginous tissue which leads to regeneration based on an endochondral ossification, a mechanism that is slower that its

Regarding the duration of this period, there is no consensus and several studies report variable periods from 0 to 21 days [1, 7, 8, 10]. There are several factors that influence the appropriate latency period, such as: age, the osteotomy localization, the soft tissue trauma or the existence of a primary pathology. A longer latency period may allow a premature consolidation, being then necessary to produce another fracture in order to continue the lengthening. And a shorter latency period might predispose to a bone non-union [3]. In Veterinary Orthopedics, the recommended latency period is 2–3 days for immature animal or 5–7 days to mature

During the distraction period, the bone segments undergo a stable and constant tension force, becoming metabolically active. The formation of bone tissue occurs

animal [1], inferior to the usual 5–10 days reported in humans [3].

*DOI: http://dx.doi.org/10.5772/intechopen.89157*

compared with the other devices [18].

**4. Latency period**

instability during the adjustment period [19].

and endosteal revascularization [7, 10, 20].

intramembranous counterpart [8].

**5. Distraction period**

smaller when compared to more rigid fixations [2].

*Distraction Osteogenesis: Biological Principles and Its Application in Companion Animals DOI: http://dx.doi.org/10.5772/intechopen.89157*

tissue inducting micro-movements along the axial axis [14–16]. A stable external fixator with less stiffness decreases the time to achieve bone consolidation. Moreover, the time of consolidation with low mechanical score (less rigid) is smaller when compared to more rigid fixations [2].

Kusec and colleagues compared the bone tissue formed by DO using a unilateral distractor and an Ilizarov distractor, in a population of 15 German Shepherd dogs. No histological or radiographic differences were found on the newly formed bone tissue. The regeneration progressed in centripetally from the cortex and the intramembranous ossification was predominant at the medullar portion of the distraction focus [17]. The Ilizarov fixator, comparing to Wagner, Orthofix, and Oxford unilateral frames, is also flexible with a consistent stiffness to bending moments in anteroposterior and lateral planes. Moreover, the Ilizarov fixator is more resistant to axial compression with increasing load and is more flexible in the axial direction compared with the other devices [18].

During bone lengthening, the distraction moment where the screws are tightened or loosened in the external device frame may create instability on the distraction focus and therefore adversely affect the procedure. The use of new compounds, such as highly dense plastics, interconnected with metal alloys, helps to prevent instability during the adjustment period [19].

### **4. Latency period**

*Clinical Implementation of Bone Regeneration and Maintenance*

**2. Osteotomy and corticotomy**

latency period will be applied, and (iv) the distraction rate (DR) must be appropriate for the level and type of bone in which osteogenesis is being performed [5]. After the separation of both segments, three temporal phases of DO can be

The DO procedure begins with the transverse section at a diaphyseal or metaphyseal level of the long bone to be elongated. Ilizarov described three methods to create fractures, including osteotomy, corticotomy, and osteoclasis. The osteogenic potential of the osteotomy or corticotomy depends on three main factors: the localization in bone, the type of technique used, and the latency period subsequently applied [6, 7]. Regarding the localization, some researchers in the past referred that the bone lengthening should be performed in the middle of the diaphysis of the long bone, and when necessary elongation was obtained, a bone graft from the ilium crest could be applied on the distraction focus to promote its consolidation. Later, Ilizarov recognized the metaphysis as the ideal site for the osteotomy, due to its massive trabecular bone area, rich in collateral vascularization, and higher potential for fracture recovery. Other researchers compared the regenerated bone quality at the diaphysis and metaphysis after DO, while using different latency periods. In the metaphysis, latency periods of 0 and 7 days allowed a greater osteogenesis and a faster remodeling and consolidation, when compared to the diaphysis elongation. A latency period of 14–21 days was associated with a premature consolidation in both regions. Bone mineralization of the newly formed tissue was faster at the metaphysis than at the diaphysis. Curiously, when there was no latency period, the distraction was successful and the consolidation faster. The latency of 7 days did not reveal the risk of premature consolidation; however, the consolidation and bone formation were slower than where there was no latency period. *Post mortem* torsion and bending test revealed that the bone tissue elongated on the metaphysis was tougher and more resistant. Histologically, the osteogenesis is observed to be based on intra-membranous ossification and, when a longer latency period is performed, increased proliferation of cartilaginous tissue at the osteotomy focus is detected, resulting in an endochondral ossification which may end up resulting in a slower process. The same study revealed that the metaphysis has more viable characteristics for the DO than the diaphysis [8]. Kojimoto and collaborators showed, in rabbits, the importance of the periosteum, referring that when it is removed, a bone callus is not formed and the bone lengthening can fail [9]. Ilizarov considered the preservation of the periosteum, and the medulla vascularization as mandatory to obtain better results on a DO [7, 10, 11]. Ilizarov developed the subperiostal osteotomy technique in which the anterior, medial, and lateral portions of the cortex are sectioned, and the posterior side is the manually fractured, thus preserving the medullar vasculature. Although Ilizarov defends the importance of

defined: latency period, distraction period, and consolidation period [3].

the medullar vasculature, other authors question its importance [9, 12, 13].

The distraction is performed using an external fixation system, and this can be a circular Ilizarov or and longitudinal monoplane unilateral frame [3]. It is imperative to keep an adequate stabilization of the fracture, its alignment, and

The external fixator frame rigidity must prevent unnecessary micro-movements at the osteotomy site, but, at the same time, it should be compliant to allow bone

**94**

**3. Segment stabilization**

osteodistraction [11, 14].

The latency period begins immediately after the osteotomy and extends to the beginning of the distraction. This may be characterized as a "rest" period after the corticotomy to allow a tissue response to the iatrogenic trauma. This response includes a proliferation of fibroblast and the induction of a state of periosteal reactivity, phenomena which occur at the beginning of a fracture regeneration [3]. The latency period allows an organization of the hematoma and the fibrous tissue matrix, which will serve as a mold to the osteoblast proliferation, that on the first 24 hours produce osteoid at the bone surfaces. This period also allows a periosteal and endosteal revascularization [7, 10, 20].

In rabbits, the importance of the latency period was demonstrated in a tibial DO. A 7-day latency period allowed a greater regeneration at the distraction focus and increased vasculature, in opposition to a DO without latency period characterized by a fibrous tissue formation [21]. Other studies showed that the existence of a latency period allows the formation of cartilaginous tissue which leads to regeneration based on an endochondral ossification, a mechanism that is slower that its intramembranous counterpart [8].

Regarding the duration of this period, there is no consensus and several studies report variable periods from 0 to 21 days [1, 7, 8, 10]. There are several factors that influence the appropriate latency period, such as: age, the osteotomy localization, the soft tissue trauma or the existence of a primary pathology. A longer latency period may allow a premature consolidation, being then necessary to produce another fracture in order to continue the lengthening. And a shorter latency period might predispose to a bone non-union [3]. In Veterinary Orthopedics, the recommended latency period is 2–3 days for immature animal or 5–7 days to mature animal [1], inferior to the usual 5–10 days reported in humans [3].

### **5. Distraction period**

During the distraction period, the bone segments undergo a stable and constant tension force, becoming metabolically active. The formation of bone tissue occurs

along the distractive stress line, in the lengthening focus at the extremities of both bone segments. During this regenerative process, the bone tissue formation can reach 200–400 μm/day, which is 4–8 times superior to the physiological bone growth that occurs in the physis of a healthy growing dog [22].

With the distraction onset, tensile forces develop at the fracture focus, while at the same time collagen is deposited by proliferating fibroblast and organized into linear fibrils. This tissue becomes radiographically visible after 7–14 days of distraction, and with the continuous process, a radiolucency zone is formed at the center of the fracture focus, the fibrous interzone (FIZ). This zone divides the regenerated bone in equal parts, and it is rich in chondrocytes, fibroblast, and ovoid cell morphologically intermediate between a fibroblast and osteoblast. The FIZ remains avascular during most part of the distraction, after its completion, it is rapidly vascularized and mineralized during the consolidation period [3]. When the FIZ cells differentiate in osteoblasts, they begin to deposit bone matrix forming the micro-column formation zones (MCFZ). These micro-columns are similar to stalactites and stalagmites and are identified as cones of 150–200 μm. This mineralization proceeds longitudinally along the collagen fibers, parallel to the distraction forces. Between the FIZ and MCFZ, a connective tissue is formed, and this contains highly proliferative cells identical to those that arise in a primary ossification center [3].The fibroblast and osteoblast are arranged along the longitudinal collagen fibers at the distraction site and the later deposit osteoid directly into this fibrils [2] (**Figure 1**).

Although controversial, most histological studies regarding Ilizarov's method confirm that bone formation during a DO is primarily based in intramembranous ossification [8, 23]. In humans and in animal models of osteodistraction on both long bones and mandible, performed in dogs, rabbits, and sheep, intramembranous ossification prevails over its endochondral counterpart [9, 22, 24, 25], mainly on the ending stage [26]; however, three distinct ossification methods have already been identified. Endochondral ossification can be identified in all DO periods [9, 24, 27] and it is usually identified at the FIZ junctions and at new mineralized membranes originated from the corticotomy site [26, 28]. The ossification ratio between an intramembranous and endochondral ossification is 5–1, respectively [18, 26].

A third ossification phenomenon was histologically identified and termed transchondroid ossification, characterized by a bone formed from cells similar to chondrocytes and with a transition from fibrous tissue to chondroid bone tissue, a tissue intermediate between bone and cartilage, which undergoes a gradual transition to bone tissue without a blood capillary invasion [23, 28]. Other authors have

#### **Figure 1.**

*Representative radiographic images of a distraction osteogenesis procedure performed in a 7-month-old female Greyhound dog due to a premature distal ulnar physis closure with proximal consequences in elbow joint. (A) Lateral view of the lower right thoracic limb. (B) Cranial view of the limb after the application of the distractor in the ulna. (C) Lateral view upon 11 days of distraction. (D) Lateral view at the end of the consolidation period and after the removal of the distractor. (E) After ulnar bone consolidation and lengthening, a realignment of the radius with an osteosynthesis plate was performed to fully rehabilitate the limb.*

**97**

*Distraction Osteogenesis: Biological Principles and Its Application in Companion Animals*

shown that cells similar to hypertrophied chondrocyte go through an osteogenic differentiation with deposition of type 1 and type 2 collagen fibers [29]. The cartilage that forms during a DO is usually located near the periosteum, but not within the

*Representative histologic images of a mandibular bone after distraction osteogenesis. (A) Distraction area successfully filled with new regenerated bone. (B) Bone defect occupied by connective tissue, a failure probably due to mobility of one of the fragments. Magnification ×40, Levai Laczko staining. Courtesy of Prof. Fernando*

*Muñoz, Department of Clinical Veterinarian Sciences, University of Santiago de Compostela.*

During the distraction period occurs an enormous angiogenic response. At the lengthening site, a peak of blood circulation nine times superior to that of normal bone tissue may occur. This hypervolemia persists for a significant amount of time, as it was shown that 17 weeks after the procedure the local volemia remains twice

It is believed that bone regeneration occurs in response to a slow and stable mechanical tensile force, applied to the bone callus and under which the living tissues become metabolically active, this phenomenon is called mechano-transduction [7, 10]. Ilizarov's experiments demonstrated that mitochondria of the skeletal muscular tissue hypertrophied and become more active, resulting in increased

During the distraction period, it is advised to do a radiographic assessment of the patient every 7–10 days, in order to evaluate the regenerated bone tissue, and if necessary, readjust the distraction rate (DR) [1]. Once the idealized bone length is achieved, the distraction ends. Marking the beginning of the consolidation period

The distraction rate (DR), defined as the tension gradually applied to the bone, is measured in millimeters per day, the normal being 1 mm/day. However, this may vary according with the bone or the site of the bone we want to lengthen [3].

The total amount of distraction performed daily, the DR, is based on the same factors that should be considered for the ideal latency period [7, 10]. The typical DR in Veterinary Medicine should range from 0.75 to 2 mm/day, which is similar to what happens in Human Orthopedics [31–33]. Variables like age, osteotomy technique, and localization will influence the choice of a correct DR. We can correlate excessive DRs with muscular contractures and articular subluxations [34, 35]. The choice of an appropriate DR is essential in the prevention of premature consolidation of the regenerated tissue and soft tissue damage, as well as in the maintenance

Ilizarov proposed an ideal DR of 1 mm/day for bone regeneration, and he based himself on his study in 120 dogs, using DR of 0.5, 1, and 2 mm/day. When using 0.5 mm/day, he noticed an increase in premature closures. And while using a DR of 2 mm/day Ilizarov reported increased tissue damage due to exceeding the tissues' revascularization capacity [14]. Recent studies suggest that DR between 0.5 and 2 mm/day

limits of the cortex on the distraction focus [3] (**Figure 2**).

cellular volume and functional activity of the cell's nucleus [10].

where the bone and osteoid are mineralized and remodeled [3].

**6. Distraction rate and distraction rhythm**

of articular congruity and biomechanical stability [1].

the normal value [23, 30].

**Figure 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.89157*

*Distraction Osteogenesis: Biological Principles and Its Application in Companion Animals DOI: http://dx.doi.org/10.5772/intechopen.89157*

#### **Figure 2.**

*Clinical Implementation of Bone Regeneration and Maintenance*

growth that occurs in the physis of a healthy growing dog [22].

along the distractive stress line, in the lengthening focus at the extremities of both bone segments. During this regenerative process, the bone tissue formation can reach 200–400 μm/day, which is 4–8 times superior to the physiological bone

With the distraction onset, tensile forces develop at the fracture focus, while at the same time collagen is deposited by proliferating fibroblast and organized into linear fibrils. This tissue becomes radiographically visible after 7–14 days of distraction, and with the continuous process, a radiolucency zone is formed at the center of the fracture focus, the fibrous interzone (FIZ). This zone divides the regenerated bone in equal parts, and it is rich in chondrocytes, fibroblast, and ovoid cell morphologically intermediate between a fibroblast and osteoblast. The FIZ remains avascular during most part of the distraction, after its completion, it is rapidly vascularized and mineralized during the consolidation period [3]. When the FIZ cells differentiate in osteoblasts, they begin to deposit bone matrix forming the micro-column formation zones (MCFZ). These micro-columns are similar to stalactites and stalagmites and are identified as cones of 150–200 μm. This mineralization proceeds longitudinally along the collagen fibers, parallel to the distraction forces. Between the FIZ and MCFZ, a connective tissue is formed, and this contains highly proliferative cells identical to those that arise in a primary ossification center [3].The fibroblast and osteoblast are arranged along the longitudinal collagen fibers at the distraction site and the later deposit osteoid directly into this fibrils [2] (**Figure 1**). Although controversial, most histological studies regarding Ilizarov's method confirm that bone formation during a DO is primarily based in intramembranous ossification [8, 23]. In humans and in animal models of osteodistraction on both long bones and mandible, performed in dogs, rabbits, and sheep, intramembranous ossification prevails over its endochondral counterpart [9, 22, 24, 25], mainly on the ending stage [26]; however, three distinct ossification methods have already been identified. Endochondral ossification can be identified in all DO periods [9, 24, 27] and it is usually identified at the FIZ junctions and at new mineralized membranes originated from the corticotomy site [26, 28]. The ossification ratio between an intramembranous and endochondral ossification is 5–1, respectively [18, 26]. A third ossification phenomenon was histologically identified and termed transchondroid ossification, characterized by a bone formed from cells similar to chondrocytes and with a transition from fibrous tissue to chondroid bone tissue, a tissue intermediate between bone and cartilage, which undergoes a gradual transition to bone tissue without a blood capillary invasion [23, 28]. Other authors have

*Representative radiographic images of a distraction osteogenesis procedure performed in a 7-month-old female Greyhound dog due to a premature distal ulnar physis closure with proximal consequences in elbow joint. (A) Lateral view of the lower right thoracic limb. (B) Cranial view of the limb after the application of the distractor in the ulna. (C) Lateral view upon 11 days of distraction. (D) Lateral view at the end of the consolidation period and after the removal of the distractor. (E) After ulnar bone consolidation and lengthening, a realignment of the radius with an osteosynthesis plate was performed to fully rehabilitate the limb.*

**96**

**Figure 1.**

*Representative histologic images of a mandibular bone after distraction osteogenesis. (A) Distraction area successfully filled with new regenerated bone. (B) Bone defect occupied by connective tissue, a failure probably due to mobility of one of the fragments. Magnification ×40, Levai Laczko staining. Courtesy of Prof. Fernando Muñoz, Department of Clinical Veterinarian Sciences, University of Santiago de Compostela.*

shown that cells similar to hypertrophied chondrocyte go through an osteogenic differentiation with deposition of type 1 and type 2 collagen fibers [29]. The cartilage that forms during a DO is usually located near the periosteum, but not within the limits of the cortex on the distraction focus [3] (**Figure 2**).

During the distraction period occurs an enormous angiogenic response. At the lengthening site, a peak of blood circulation nine times superior to that of normal bone tissue may occur. This hypervolemia persists for a significant amount of time, as it was shown that 17 weeks after the procedure the local volemia remains twice the normal value [23, 30].

It is believed that bone regeneration occurs in response to a slow and stable mechanical tensile force, applied to the bone callus and under which the living tissues become metabolically active, this phenomenon is called mechano-transduction [7, 10]. Ilizarov's experiments demonstrated that mitochondria of the skeletal muscular tissue hypertrophied and become more active, resulting in increased cellular volume and functional activity of the cell's nucleus [10].

During the distraction period, it is advised to do a radiographic assessment of the patient every 7–10 days, in order to evaluate the regenerated bone tissue, and if necessary, readjust the distraction rate (DR) [1]. Once the idealized bone length is achieved, the distraction ends. Marking the beginning of the consolidation period where the bone and osteoid are mineralized and remodeled [3].

### **6. Distraction rate and distraction rhythm**

The distraction rate (DR), defined as the tension gradually applied to the bone, is measured in millimeters per day, the normal being 1 mm/day. However, this may vary according with the bone or the site of the bone we want to lengthen [3].

The total amount of distraction performed daily, the DR, is based on the same factors that should be considered for the ideal latency period [7, 10]. The typical DR in Veterinary Medicine should range from 0.75 to 2 mm/day, which is similar to what happens in Human Orthopedics [31–33]. Variables like age, osteotomy technique, and localization will influence the choice of a correct DR. We can correlate excessive DRs with muscular contractures and articular subluxations [34, 35]. The choice of an appropriate DR is essential in the prevention of premature consolidation of the regenerated tissue and soft tissue damage, as well as in the maintenance of articular congruity and biomechanical stability [1].

Ilizarov proposed an ideal DR of 1 mm/day for bone regeneration, and he based himself on his study in 120 dogs, using DR of 0.5, 1, and 2 mm/day. When using 0.5 mm/day, he noticed an increase in premature closures. And while using a DR of 2 mm/day Ilizarov reported increased tissue damage due to exceeding the tissues' revascularization capacity [14]. Recent studies suggest that DR between 0.5 and 2 mm/day

are appropriate, and that the ideal DR must be based on individual characteristics such as age, osteotomy site, and need for angular correction [12, 35].

The distraction rhythm (DRy), the number of lengthening times made per day, influences the quality and quantity of the regenerated bone tissue and is important in the preservation of the soft tissue integrity during the procedure [7, 10, 34]. Ilizarov observed, using a canine model, that by using an automatic distractor capable of performing a DRy of 60 times per day, would produce a significantly better quality of bone when compared with DRy of 1–4 times per day. A DR of 1 mm a day with a DRy of 4 times a day was determined as ideal [7, 10]. In a goat model of tibia lengthening, DRy of 1, 4, and 720 times per day would not affect the strength, rigidity, and histomorphometric characteristic of the regenerated bone and would not affect the somatosensory potential of the peripheral nerves [34, 36]. Another study using the same animal model concluded that increasing the DRy would result in less muscular degeneration [39]. In Veterinary Medicine, it is recommended DRy of 2–4 times per day [9, 18, 31, 33].


**Author details**

```
Goharik Petrosyan
Plekhanov Russian University of Economics Yerevan Branch, Member of Armenian
Mathematical Union, ASPU, ISEC of NAS RA, Yerevan, Armenia
```
\*Address all correspondence to<EMAIL_ADDRESS><EMAIL_ADDRESS>
© 2019 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.