\r\n\tRecent statistics confirm that business increasingly sees sustainability as a critical and essential element in their business strategy. For example, an increasingly competitive environment can create significant problems for many organizations as they struggle to adapt to change. As a result, many organizations fail to create the necessary conditions that can lead to long-term sustainable development, which affects the capabilities of employees.\r\n
\r\n\tOrganizations and business are increasingly required to contribute to social and environmental sustainability or, better yet, that business themselves become sustainable. The world is increasingly aware of this demand, and there is no other alternative. The discussion, therefore, should not be on whether or not they should be sustainable, but on the scope of sustainable ideas and how to integrate them into a company's strategy. In this sense, this book will represent an important contribution.
\r\n\tThis book will intend to provide the reader with an overview of the current state of sustainability in organizations and business, presenting an easy-to-follow format. First, we will focus on the most important developments around the concept, theories, and the evaluation of sustainability, followed by models of innovation and sustainability; as well as drivers of sustainable development. Lastly, we will describe some models and present new perspectives for sustainable development. Ultimately, we want to present an image that, although not perfect, provides useful information that can help managers make future decisions.
\r\n\tThe relevance of this book will lie in combining academic rigour with a practical approach. The book will contain examples, good practices, as well as reflections, which are useful for all of us who are dedicated and passionate about this topic, whether from an academic or management perspective.
Some of the downsides of GPS are listed in . Among these are several limitations which are relevant to this chapter. The weak intensity signal causes GPS to be less applicable for cases where stable navigating is mandatory or cases where navigating at indoor and covered areas. The low granularity of the signal accuracy makes navigation in crowded cities where landmarks are so close such that GPS is not able to differentiate among them and so is not effective. Furthermore, GPS signal may disperse and change its direction due to interruptions caused by skyscrapers, trees, geomagnetic storms, etc. The impact of unreliable GPS is huge especially due to the constant growing use of navigation applications such as Google Maps and Waze, which heavily rely on GPS signal. The impact may be more car accidents in cases where required information is missed exactly at the time it is critical and useful for driving continuation. GPS signal is not enough for covering all navigation instances. Local and timely knowledge is required for updated and accurate information to be able to properly react instantly when obstacles appear in the road ahead, for example, whether a deep pit or a flooding road is likely to be or if the road is closed. To reduce the dependency on GPS, several methods and technologies have been proposed, such as detailed map information, data from sensors, vision-based measurements, stop lines, and GPS-fused SLAM technologies.
A geographic information system (GIS) is a system designed to capture, store, manipulate, analyze, manage, and present all types of geographical data. Many electronic navigation systems deliver its road-guiding instructions using just verbal commands referring to the associated electronic map displayed to the user. This approach assumes the user familiarity with street maps and road networks, which sometimes is not so. In addition, there are places where street maps are not commonly used and instead landmarks are used allowing the intuitive navigation by recognizable and memoizable views along the route. The introduction of buildings as landmarks together with corresponding spoken instructions is a step towards a more natural navigation. The integration of GPS and GIS provides this capability. The main problem lies in identifying suitable landmarks and evaluating their usefulness for navigation instructions. Existing databases can help to tackle this problem and be an integrated part of most navigation applications. For example, Brondeel et al.  used GPS, GIS, and accelerometer data to collect data of trips and proposed a prediction model for transportation modes with high correction rate. ResZexue et al.  developed a logistics distribution manager (LDM) software and a smart machine (SM) system. It is based on fusing GPS, GIS, Big Data, Internet+, and other technologies to effectively apply its attributes and benefits for achieving a robust information management system for the logistics industry. The resulting logistics facility has shorter distribution time, improved operational competitiveness, optimized the workflow of the logistics distribution efficiency, and saved cost. These examples demonstrate the level of improvements we can expect by integrating GPS and GIS as well as the IoT, mobile phones, and other current technologies.
GPS positions provided via phone are generated using multiple different methods, resulting in highly variable performance. Performance depends on the smartphone attributes, the cell network, availability of GPS satellites, and line of sight to these satellites. The time from turning on the smartphone to getting GPS coordinates is relatively long. To accelerate it, a variety of techniques got used. Some phones have incomplete GPS hardware, requiring a cell network to function. The quality of the GPS antenna determines the duration until the device will get a lock. For example, the S3 Mini device has relatively good GPS hardware, including GLONASS and A-GPS support.
Urban canyons, sky blockage, and multipath errors affect the quality and accuracy of GNSS/GPS. Public transportation in modern cities may have hundreds of routes and thousands of bus stops, exchange points, and busses. These two factors make urban bus systems hard to follow and complex to navigate. Mobile applications provide passengers with transport planning tools and find the optimal route, next bus number, arrival time, and ride duration. More advanced applications provide also micro-navigation-based decisions, such as current position and bus number, the number of stops left till arrival, and exchange to a better route. Micro-navigation decisions are highly contextual and depend not just on time and location but also on the user’s current transport mode, waiting for a bus or riding on a bus. Emerging technology is where accuracy and robustness are critical requirements for safe guidance and stable control. GNSS accuracy can be significantly improved using several techniques such as differential GNSS (DGNSS), augmented GNSS, and precise positioning services (PPS). These techniques add complexity and additional cost. Multi-constellation GNSS also enhances the accuracy by increasing the number of visible satellites. In dense urban areas where high buildings are common, the geometry of visible satellites often results into high uncertainty in the vehicle’s GNSS position estimate resulting in performance in dense urban areas still being challenging.
Urban Bus Navigator (UBN) is a system infrastructure that connects passengers’ mobile smartphones with Wi-Fi-enabled busses, gaining real-time information about the journey and transport situations of passengers . A key feature of UBN is a semantic bus ride detection that identifies the concrete bus and route the passenger is riding on, providing continuous, just-in-time dynamic rerouting and end-to-end guidance for bus passengers. Technical tests indicate the feasibility of semantic bus ride detection, while user tests revealed recommendations for effective user support with micro-navigation. The system elements include semantic bus ride detection using a Wi-Fi-based recognition system and a dynamic trip tracking. The semantic bus ride detection combined with the phone’s GPS is used to monitor the passenger’s trip progress. Deviations are immediately recognized and trigger replanning the trip, resulting a new set of navigation instructions for the passenger. The architecture is composed of Wi-Fi for proximity detection of busses by the passenger’s mobile phone, a smartphone application for trip planning using macro-navigation, a context-aware trip hints using micro-navigation, context sensing, bus ride recognition, and trip tracking.
This urban navigation is based on detecting and mitigating GNSS errors caused by condensed high buildings interfering signals going through . It is using a map-aided adaptive fusion scheme. The method estimates the current active map segment using dead-reckoning and robust map-matching algorithms modeling the vehicle state history, road geometry, and map topology in a hidden Markov model (HMM). The Viterbi algorithm decodes the HMM model and selects the most likely map segment. The projection of vehicle states onto the map segment is used as a supplementary position update to the integration filter. The solution framework has been developed and tested on a land-based vehicular platform. The results show a reliably mitigate biased GNSS position and accurate map segment selection in complex intersections, forks, and joins. In contrast to common existing adaptive Kalman filter methods, this solution does not depend on redundant pseudo-ranges and residuals, which makes it suitable for use with arbitrary noise characteristics and varied integration schemes.
Urban environments offer a challenging scenario for autonomous driving . The proposed solution allows autonomously navigate urban roadways with minimum a priori map or GPS. Localization is achieved by Kalman filter extended with odometry, compass, and sparse landmark measurement updates. Navigation is accomplished by a compass-based navigation control law. Experiments validate simulated results and demonstrate that, for given conditions, an expected range can be found for a given success rate.
The architecture contains steering and speed controllers, an object tracker, a path generator, a pose estimator, and a navigation algorithm using sensors allowing real-time control. High-level localization is provided by the pose estimator, which utilizes only odometry measurements, compass measurements, and sparse map-based measurements. The sparse map-based measurements generated from computer vision methods compare raw camera images to landmark images contained within a sparse map. The roadway scene includes lane line markings, road signs, traffic lights, and other sensor measurements. The scene information and the inertial pose estimate are fed into a navigation algorithm to determine the best route required to reach the target. This navigation scheme is provided by a compass-based navigation control law.
Common navigation technologies assume navigation on a surface with two-dimension (2D), flat land area. Navigation in three-dimension (3D) is much more complicated requiring at least new technologies to complement the existing 2D navigation technologies.
In this section we present a low-computational method for state estimator enabling autonomous flight of micro aerial vehicles . All the estimation and control tasks are solved on board and in real time on a simple computational unit. The state estimator fuses observations from an inertial measurement unit, an optical flow smart camera, and a time-of-flight range sensor. The smart camera provides optical flow measurements and odometry estimation, avoiding the need for image processing, usable during flight times of several minutes. A nonlinear controller operating in the special Euclidean group SE(3) can drive, based on the estimated vehicle’s state, a quadrotor platform in 3D space guaranteeing the asymptotic stability of 3D position and heading. The approach is validated through simulations and experimental result.
Weiss  developed a vision-based navigation system for micro helicopters operating in large and unknown environments. It is based on vision-based methods and a sensor fusion approach for state estimation and sensor self-calibration of sensors and with their different availability during flight. This is enabled by an onboard camera, real-time motion sensor, and vision algorithms. It renders the camera and an onboard multi-sensor fusion framework capable to estimate at the same time the vehicle’s pose and the inter-sensor calibration for continuous operation. It runs at linear time to the number of key frames captured in a previously visited area. To maintain constant computational complexity, improve performance, and increase scalability and reliability, the computationally expensive vision part is replaced by the final calculated camera pose.
Traditional space positioning and navigation are based on large satellites flying in a semi-fixed orbit and so are costly and less flexible . Recent developments of low-mass, low-power navigation sensors and the popularity of smaller satellites, a new approach of having many tiny spacecrafts flying in clusters under controlled configurations utilizing its cumulative power to perform necessary assignments. To keep stable but changeable configurations, positioning, attitude, and intersatellite navigation are used. For the determination of relative position and attitude between the formation flying satellites, Carrier-phase differential GPS (CDGPS) is used, where range coefficients, GPS differential corrections, and other data are exchanged among spacecrafts, enhancing the precision of the ranging and navigation functions. The CDGPS communicates the NAVSTAR GPS constellation to provide precise measures of the relative attitude, the positions between vehicles, and attitude in the formation.
Pedestrian navigation services enable people to retrieve precise instructions to reach a specific location. As the spatial behavior of people on foot differs in many ways from the driver’s performance, common concepts for car navigation services are not suitable for pedestrian navigation. Cars use paved roads with clear borderlines and road signs, and so keeping the car on track is its main role, neglecting obstacles and hazards, unless it is integrated with a social network. However, pedestrians, unlike like cars, may not follow the defined road. This makes personal navigation more complicated and forces us adding special features required for safe navigation. Pedestrian navigation requires very accurate, high-resolution, and real-time response . Solely GPS does not support last moment route changes, such as road detours, significant obstacles, and safety requirements. However, integrating the IoT and GPS via an application generates a solution providing accurate and safe navigation. To enable it, a two-stage personal navigation system is used. In the first stage, the trail is photographed by a navigated drown, and the resulting video is saved in a cloud database. In the second stage, a mobile application is loaded to the pedestrian’s mobile phone. Once the pedestrian is about to walk, it activates the mobile application which synchronizes itself with the cloud navigation database, and then instructions from the mobile phone guide the pedestrian along the trail-walk. A more advanced system contains the two stages within the mobile application. The mobile video camera is activated and captures the trail images in front of the pedestrian, processes it, and guides the pedestrian accordingly. In case of an upcoming obstacle, the application proposes the safest and most effective detour and guides the pedestrian accordingly.
Personal navigation systems are very accurate and safe, operate indoor and outdoor, and are available as long as the mobile phone is connected, and its internal storage is big enough. It provides spatial information for climbing, wandering, or tramping users. It is used for locating casualties, as well as for self-orientation of rescue teams in areas with low visibility. In military and security operations, localization and information technologies are used by soldiers to self-locate, collect, and collate. A similar implementation with the same functionality is a walking stick with embedded micro devices and software as described above and a wearable Bluetooth headset with an embedded camera in front of it.
Navigation in cities is commonly done by the target address: zip-code, street, and house number. However, in cases where people do not use street and house number as an address but rather use landmarks to identify the route to the target as well as the target location , by combining CIS and GPS, the desired landmarks coordinates are loaded to the cloud database, and the corresponding navigation application is modified to identify the landmarks on ground.
A landmark-based navigation system is composed of a video camera to obtain and analyze pedestrian paths, selected reliable landmarks along the main routes, a routing table containing all relevant origins and destinations within the site, positions of view and orientations to assert maximal coverage of interesting spots, thousands of partial routes for the entire recording period, and the detected stops over a whole day for different definitions of a stop. Based on the defined sections and the landmarks and decision points, a routing table is created to define navigational instructions from each origin in the station to each possible destination. Table columns correspond to the original landmarks and the decision points; rows correspond to destination landmarks. The identified landmarks and the defined route instructions are used to develop an audio guiding system using speech recognition and text-to-speech software. The audio guiding system employs verbalisms that are as distinct and clearly recognizable as the visual landmarks and that the users can intuitively combine the description with what they see.
A micro electrical mechanical system (MEMS)  is a family of thumbnail technologies enabling a wide variety of advanced and innovative applications. When such device is mounted on a shoe, it collects the number of steps, average step width, and walking directions. This data is constantly collected and processed, and via signals it guides the person wearing the shoe. Due to the magnetic field, some navigation errors may occur; a special filter offsets it by using a special filter. Experiments show that this approach is applicable and efficient.
Indoor navigation systems became popular due to the lack of GPS signals indoors and the increase in navigation needs especially in small areas, such as parking garages and huge complex of buildings. Several indoors navigation systems have already been implemented. Each of them is based on a different technology that complies with the specific requirements and constraints of the location it is expected to navigate in. We assume that each solution has technical and usability limitations. It helps tracking objects by using wireless concepts, optical tracking, ultrasound techniques, sensors, infrared (IR), ultra-wide band (UWB), Wireless Local Area Networks (WLANs), Wi-Fi, Bluetooth, radio frequency identification (RFID), assisted GPS (A-GPS), and more. Most solutions have limited capabilities, accuracy, unreliability, design complexity, low security, and high configuration costs.
NFC technology allows communication over short-range, mobile, and wireless conditions. NFC communication happens when two NFC-capable devices are close to each other. Users use their NFC mobiles to interact with an NFC tag or another NFC mobile. NFC-based indoor navigation system enables users to navigate through a complex of buildings by touching NFC tags spread around and orienting users to the destination . NFC internal has considerable advantages to indoor navigation systems in terms of security, privacy, cost, performance, robustness, complexity, and commercial availability. The application orients the user by receiving the destination name and touching the mobile device to the NFC tags and so navigates to the desired destination.
Indoor micro-navigation systems for enclosed parking garages  are based on car-to-infrastructure communication providing layout information of the car park and the coordinates of the destination parking lot. It uses unique signal rates. In case a car is detected, the system calculates its position and transmits data to a vehicle to substitute the internal positioning system. With this information the vehicle is guided. Integration to the outdoor navigation system is available to allow smooth transition from/to outdoor/indoor.
In this section we introduce a quadrotor that performs autonomous navigation in complex indoor and outdoor environments . An operator selects target positions in the onboard map, and the system autonomously plans flights to these locations. An onboard stereo camera and an inertial measurement unit (IMU) are the only sensors. The system is independent of external navigation aids like GPS. All navigation tasks are implemented onboard the system. The system is based on FPGA-dense stereo matching images using semi-global matching, locally drift-free visual odometry with key frames and sensor data fusion. It utilizes the available depth images from stereo matching. To save processing time and make large movements or rather low frame rates possible, the system works only on features. A wireless connection is used for sending images and a 3D map to the operator and to receive target locations. The results of a complex, autonomous indoor/outdoor flight support this approach. The position is controlled by the estimated motion of the sensor. To enable it, a state machine controller, a tracking position system, and a reference generator are implemented. The reference generator is used to create smooth position, velocity, acceleration, and a tracking controller based on a list of waypoints. The flown path is composed of straight line segments between any two waypoints.
A comprehensive automated navigation system must incorporate effective tools for detecting road obstacles and instantly propose the optimal alternate route bypassing the detected obstacle. It combines optimal route finding, real-time route inspection, and route adjustments to ensure safe navigation. The following are three examples utilizing advanced technologies such as computer vision, fuzzy logic, and context-aware. More examples can be found in .
Unmanned aerial vehicles (UAVs) use vision as the principal  source of information through the monocular onboard camera. The system compares the obtained image to the obstacles to be avoided. Micro aerial vehicle (MAV), to detect and avoid obstacles in an unknown controlled environment. Only the feature points are compared with the same type of contrast, achieving a lower computational cost without reducing the descriptor performance. After detecting the obstacle, the vehicle should recover the path. The algorithm starts when the vehicle is closer to the obstacle than the distance allowed. The limit area value is experimentally obtained defining the dimensions of obstacles in pixels at a specific distance. The output of the control law moves the vehicle away from the center of the obstacle avoiding it. If the error is less than zero, the vehicle moves to the right side. Detouring of permanent obstacles, a preliminary process is applied to scan the route and correct it such that the corrected route already considers all known obstacles and skips them.
Mobile robots perform tasks such as rescue and patrolling. It can navigate intelligently by using sensor control techniques . Several techniques have been applied for robot navigation and obstacle avoidance. Fuzzy logic technique is inspired by human perception-based reasoning. It has been applied to behavior-based robot navigation and obstacle avoidance in unknown environments. It trains the robot to navigate by receiving the obstacle distance from a group of sensors. A reinforcement learning method and a genetic algorithm optimize the fuzzy controller for improving its performance while the robot moves. Comparing the performance of different functions such as triangular, trapezoidal, and Gaussian for mobile robot navigation shows that the Gaussian membership function is more efficient for navigation.
A similar concept is using neural network learning method to construct a path planning and collision-free for robots. Real-time collision-free path planning is more difficult when the robot is moving in a dynamic and unstructured environment.
The system is composed of three embedded components; a map manager, a motion tracker, and a hindrance dodging . The map manager generates semantic maps from a given building model. The hindrance dodging detects visible objects lying on the road and suggests a safe bypass route to the target location. A developed prototype performed very well proving that this navigation system is effective and efficient.
This chapter introduces various complementing navigation concepts and implementations, integrating advanced technologies and improving and expanding existing traditional navigation solutions. The outcome is a wide variety of solutions for cases where standard navigation technologies such as GPS are less effective or not applicable. We presented several areas where various technologies have been tailored to specific problems. For each problem we described different cases with unique technologies and implementations.
Bone is living tissue that is the hardest among other connective tissues in the body, consists of 50% water. The solid part remainder consisting of various minerals, especially 76% of calcium salt and 33% of cellular material. Bone has vascular tissue and cellular activity products, especially during growth which is very dependent on the blood supply as basic source and hormones that greatly regulate this growth process. Bone-forming cells, osteoblasts, osteoclast play an important role in determining bone growth, thickness of the cortical layer and structural arrangement of the lamellae.
Bone continues to change its internal structure to reach the functional needs and these changes occur through the activity of osteoclasts and osteoblasts. The bone seen from its development can be divided into two processes: first is the intramembranous ossification in which bones form directly in the form of primitive mesenchymal connective tissue, such as the mandible, maxilla and skull bones. Second is the endochondral ossification in which bone tissue replaces a preexisting hyaline cartilage, for example during skull base formation. The same formative cells form two types of bone formation and the final structure is not much different.
Bone growth depends on genetic and environmental factors, including hormonal effects, diet and mechanical factors. The growth rate is not always the same in all parts, for example, faster in the proximal end than the distal humerus because the internal pattern of the spongiosum depends on the direction of bone pressure. The direction of bone formation in the epiphysis plane is determined by the direction and distribution of the pressure line. Increased thickness or width of the bone is caused by deposition of new bone in the form of circumferential lamellae under the periosteum. If bone growth continues, the lamella will be embedded behind the new bone surface and be replaced by the haversian canal system.
Bone is a tissue in which the extracellular matrix has been hardened to accommodate a supporting function. The fundamental components of bone, like all connective tissues, are cells and matrix. Although bone cells compose a small amount of the bone volume, they are crucial to the function of bones. Four types of cells are found within bone tissue: osteoblasts, osteocytes, osteogenic cells, and osteoclasts. They each unique functions and are derived from two different cell lines (Figure 1 and Table 1) [1, 2, 3, 4, 5, 6, 7].
Osteoblast synthesizes the bone matrix and are responsible for its mineralization. They are derived from osteoprogenitor cells, a mesenchymal stem cell line.
Osteocytes are inactive osteoblasts that have become trapped within the bone they have formed.
Osteoclasts break down bone matrix through phagocytosis. Predictably, they ruffled border, and the space between the osteoblast and the bone is known as Howship’s lacuna.
The balance between osteoblast and osteoclast activity governs bone turnover and ensures that bone is neither overproduced nor overdegraded. These cells build up and break down bone matrix, which is composed of:
Osteoid, which is the unmineralized matrix composed of type I collagen and gylcosaminoglycans (GAGs).
Calcium hydroxyapatite, a calcium salt crystal that give bone its strength and rigidity.
Compact bone, or cortical bone, mainly serves a mechanical function. This is the area of bone to which ligaments and tendons attach. It is thick and dense.
Trabecular bone, also known as cancellous bone or spongy bone, mainly serves a metabolic function. This type of bone is located between layers of compact bone and is thin porous. Location within the trabeculae is the bone marrow.
The epiphysis is located at the end of the long bone and is the parts of the bone that participate in joint surfaces.
The diaphysis is the shaft of the bone and has walls of cortical bone and an underlying network of trabecular bone.
The epiphyseal growth plate lies at the interface between the shaft and the epiphysis and is the region in which cartilage proliferates to cause the elongation of the bone.
The metaphysis is the area in which the shaft of the bone joins the epiphyseal growth plate.
Different areas of the bone are covered by different tissue :
The epiphysis is lined by a layer of articular cartilage, a specialized form of hyaline cartilage, which serves as protection against friction in the joints.
The outside of the diaphysis is lined by periosteum, a fibrous external layer onto which muscles, ligaments, and tendons attach.
The inside of the diaphysis, at the border between the cortical and cancellous bone and lining the trabeculae, is lined by endosteum.
Compact bone is organized as parallel columns, known as Haversian systems, which run lengthwise down the axis of long bones. These columns are composed of lamellae, concentric rings of bone, surrounding a central channel, or Haversian canal, that contains the nerves, blood vessels, and lymphatic system of the bone. The parallel Haversian canals are connected to one another by the perpendicular Volkmann’s canals.
The lamellae of the Haversian systems are created by osteoblasts. As these cells secrete matrix, they become trapped in spaces called lacunae and become known as osteocytes. Osteocytes communicate with the Haversian canal through cytoplasmic extensions that run through canaliculi, small interconnecting canals (Figure 4) [1, 2, 8, 9]:
The layers of a long bone, beginning at the external surface, are therefore:
Periosteal surface of compact bone
Outer circumferential lamellae
Compact bone (Haversian systems)
Inner circumferential lamellae
Endosteal surface of compact bone
Bone development begins with the replacement of collagenous mesenchymal tissue by bone. This results in the formation of woven bone, a primitive form of bone with randomly organized collagen fibers that is further remodeled into mature lamellar bone, which possesses regular parallel rings of collagen. Lamellar bone is then constantly remodeled by osteoclasts and osteoblasts. Based on the development of bone formation can be divided into two parts, called endochondral and intramembranous bone formation/ossification [1, 2, 3, 8].
During intramembranous bone formation, the connective tissue membrane of undifferentiated mesenchymal cells changes into bone and matrix bone cells . In the craniofacial cartilage bones, intramembranous ossification originates from nerve crest cells. The earliest evidence of intramembranous bone formation of the skull occurs in the mandible during the sixth prenatal week. In the eighth week, reinforcement center appears in the calvarial and facial areas in areas where there is a mild stress strength .
Intramembranous bone formation is found in the growth of the skull and is also found in the sphenoid and mandible even though it consists of endochondral elements, where the endochondral and intramembranous growth process occurs in the same bone. The basis for either bone formation or bone resorption is the same, regardless of the type of membrane involved.
Sometimes according to where the formation of bone tissue is classified as “periosteal” or “endosteal”. Periosteal bone always originates from intramembranous, but endosteal bone can originate from intramembranous as well as endochondral ossification, depending on the location and the way it is formed [3, 12].
An ossification center appears in the fibrous connective tissue membrane. Mesenchymal cells in the embryonic skeleton gather together and begin to differentiate into specialized cells. Some of these cells differentiate into capillaries, while others will become osteogenic cells and osteoblasts, then forming an ossification center.
Bone matrix (osteoid) is secreted within the fibrous membrane. Osteoblasts produce osteoid tissue, by means of differentiating osteoblasts from the ectomesenchyme condensation center and producing bone fibrous matrix (osteoid). Then osteoid is mineralized within a few days and trapped osteoblast become osteocytes.
Woven bone and periosteum form. The encapsulation of cells and blood vessels occur. When osteoid deposition by osteoblasts continues, the encased cells develop into osteocytes. Accumulating osteoid is laid down between embryonic blood vessels, which form a random network (instead of lamellae) of trabecular. Vascularized mesenchyme condenses on external face of the woven bone and becomes the periosteum.
Production of osteoid tissue by membrane cells: osteocytes lose their ability to contribute directly to an increase in bone size, but osteoblasts on the periosteum surface produce more osteoid tissue that thickens the tissue layer on the existing bone surface (for example, appositional bone growth). Formation of a woven bone collar that is later replaced by mature lamellar bone. Spongy bone (diploe), consisting of distinct trabeculae, persists internally and its vascular tissue becomes red marrow.
Osteoid calcification: The occurrence of bone matrix mineralization makes bones relatively impermeable to nutrients and metabolic waste. Trapped blood vessels function to supply nutrients to osteocytes as well as bone tissue and eliminate waste products.
The formation of an essential membrane of bone which includes a membrane outside the bone called the bone endosteum. Bone endosteum is very important for bone survival. Disruption of the membrane or its vascular tissue can cause bone cell death and bone loss. Bones are very sensitive to pressure. The calcified bones are hard and relatively inflexible.
The matrix or intercellular substance of the bone becomes calcified and becomes a bone in the end. Bone tissue that is found in the periosteum, endosteum, suture, and periodontal membrane (ligaments) is an example of intramembranous bone formation [3, 13].
Intramembranous bone formation occurs in two types of bone: bundle bone and lamellar bone. The bone bundle develops directly in connective tissue that has not been calcified. Osteoblasts, which are differentiated from the mesenchyme, secrete an intercellular substance containing collagen fibrils. This osteoid matrix calcifies by precipitating apatite crystals. Primary ossification centers only show minimal bone calcification density. The apatite crystal deposits are mostly irregular and structured like nets that are contained in the medullary and cortical regions. Mineralization occurs very quickly (several tens of thousands of millimeters per day) and can occur simultaneously in large areas. These apatite deposits increase with time. Bone tissue is only considered mature when the crystalized area is arranged in the same direction as collagen fibrils.
Bone tissue is divided into two, called the outer cortical and medullary regions, these two areas are destroyed by the resorption process; which goes along with further bone formation. The surrounding connective tissue will differentiate into the periosteum. The lining in the periosteum is rich in cells, has osteogenic function and contributes to the formation of thick bones as in the endosteum.
In adults, the bundle bone is usually only formed during rapid bone remodeling. This is reinforced by the presence of lamellar bone. Unlike bundle bone formation, lamellar bone development occurs only in mineralized matrix (e.g., cartilage that has calcified or bundle bone spicules). The nets in the bone bundle are filled to strengthen the lamellar bone, until compact bone is formed. Osteoblasts appear in the mineralized matrix, which then form a circle with intercellular matter surrounding the central vessels in several layers (Haversian system). Lamella bone is formed from 0.7 to 1.5 microns per day. The network is formed from complex fiber arrangements, responsible for its mechanical properties. The arrangement of apatites in the concentric layer of fibrils finally meets functional requirements. Lamellar bone depends on ongoing deposition and resorption which can be influenced by environmental factors, one of this which is orthodontic treatment.
Intramembranous bone formation from desmocranium (suture and periosteum) is mediated by mesenchymal skeletogenetic structures and is achieved through bone deposition and resorption . This development is almost entirely controlled through local epigenetic factors and local environmental factors (i.e. by muscle strength, external local pressure, brain, eyes, tongue, nerves, and indirectly by endochondral ossification). Genetic factors only have a nonspecific morphogenetic effect on intramembranous bone formation and only determine external limits and increase the number of growth periods. Anomaly disorder (especially genetically produced) can affect endochondral bone formation, so local epigenetic factors and local environmental factors, including steps of orthodontic therapy, can directly affect intramembranous bone formation [3, 11].
During endochondral ossification, the tissue that will become bone is firstly formed from cartilage, separated from the joint and epiphysis, surrounded by perichondrium which then forms the periosteum . Based on the location of mineralization, it can be divided into: Perichondral Ossification and Endochondral Ossification. Both types of ossification play an essential role in the formation of long bones where only endochondral ossification takes place in short bones. Perichondral ossification begins in the perichondrium. Mesenchymal cells from the tissue differentiate into osteoblasts, which surround bony diaphyseal before endochondral ossification, indirectly affect its direction [3, 8, 12]. Cartilage is transformed into bone is craniofacial bone that forms at the eigth prenatal week. Only bone on the cranial base and part of the skull bone derived from endochondral bone formation. Regarding to differentiate endochondral bone formation from chondrogenesis and intramembranous bone formation, five sequences of bone formation steps were determined .
Mesenchymal cells group to form a shape template of the future bone.
Mesenchymal cells differentiate into chondrocytes (cartilage cells).
Hypertrophy of chondrocytes and calcified matrix with calcified central cartilage primordium matrix formed. Chondrocytes show hypertrophic changes and calcification from the cartilage matrix continues.
Entry of blood vessels and connective tissue cells. The nutrient artery supplies the perichondrium, breaks through the nutrient foramen at the mid-region and stimulates the osteoprogenitor cells in the perichondrium to produce osteoblasts, which changes the perichondrium to the periosteum and starts the formation of ossification centers.
The periosteum continues its development and the division of cells (chondrocytes) continues as well, thereby increasing matrix production (this helps produce more length of bone).
The perichondrial membrane surrounds the surface and develops new chondroblasts.
Chondroblasts produce growth in width (appositional growth).
Cells at the center of the cartilage lyse (break apart) triggers calcification.
During endochondral bone formation, mesenchymal tissue firstly differentiates into cartilage tissue. Endochondral bone formation is morphogenetic adaptation (normal organ development) which produces continuous bone in certain areas that are prominently stressed. Therefore, this endochondral bone formation can be found in the bones associated with joint movements and some parts of the skull base. In hypertrophic cartilage cells, the matrix calcifies and the cells undergo degeneration. In cranial synchondrosis, there is proliferation in the formation of bones on both sides of the bone plate, this is distinguished by the formation of long bone epiphyses which only occurs on one side only [2, 14].
As the cartilage grows, capillaries penetrate it. This penetration initiates the transformation of the perichondrium into the bone-producing periosteum. Here, the osteoblasts form a periosteal collar of compact bone around the cartilage of the diaphysis. By the second or third month of fetal life, bone cell development and ossification ramps up and creates the primary ossification center, a region deep in the periosteal collar where ossification begins [4, 10].
While these deep changes occur, chondrocytes and cartilage continue to grow at the ends of the bone (the future epiphyses), which increase the bone length and at the same time bone also replaces cartilage in the diaphysis. By the time the fetal skeleton is fully formed, cartilage only remains at the joint surface as articular cartilage and between the diaphysis and epiphysis as the epiphyseal plate, the latter of which is responsible for the longitudinal growth of bones. After birth, this same sequence of events (matrix mineralization, death of chondrocytes, invasion of blood vessels from the periosteum, and seeding with osteogenic cells that become osteoblasts) occur in the epiphyseal regions, and each of these centers of activity is referred to as a secondary ossification center [4, 8, 10].
There are four important things about cartilage in endochondral bone formation:
Cartilage has a rigid and firm structure, but not usually calcified nature, giving three basic functions of growth (a) its flexibility can support an appropriate network structure (nose), (b) pressure tolerance in a particular place where compression occurs, (c) the location of growth in conjunction with enlarging bone (synchondrosis of the skull base and condyle cartilage).
Cartilage grows in two adjacent places (by the activity of the chondrogenic membrane) and grows in the tissues (chondrocyte cell division and the addition of its intercellular matrix).
Bone tissue is not the same as cartilage in terms of its tension adaptation and cannot grow directly in areas of high compression because its growth depends on the vascularization of bone formation covering the membrane.
Cartilage growth arises where linear growth is required toward the pressure direction, which allows the bone to lengthen to the area of strength and has not yet grown elsewhere by membrane ossification in conjunction with all periosteal and endosteal surfaces.
Membrane disorders or vascular supply problem of these essential membranes can directly result in bone cell death and ultimately bone damage. Calcified bones are generally hard and relatively inflexible and sensitive to pressure .
Cranial synchondrosis (e.g., spheno ethmoidal and spheno occipital growth) and endochondral ossification are further determined by chondrogenesis. Chondrogenesis is mainly influenced by genetic factors, similar to facial mesenchymal growth during initial embryogenesis to the differentiation phase of cartilage and cranial bone tissue.
This process is only slightly affected by local epigenetic and environmental factors. This can explain the fact that the cranial base is more resistant to deformation than desmocranium. Local epigenetic and environmental factors cannot trigger or inhibit the amount of cartilage formation. Both of these have little effect on the shape and direction of endochondral ossification. This has been analyzed especially during mandibular condyle growth.
Local epigenetics and environmental factors only affect the shape and direction of cartilage formation during endochondral ossification Considering the fact that condyle cartilage is a secondary cartilage, it is assumed that local factors provide a greater influence on the growth of mandibular condyle.
Chondrogenesis is the process by which cartilage is formed from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the extracellular matrix [5, 14].
Chondroblasts produce a matrix: the extracellular matrix produced by cartilage cells, which is firm but flexible and capable of providing a rigid support.
Cells become embed in a matrix: when the chondroblast changes to be completely embed in its own matrix material, cartilage cells turn into chondrocytes. The new chondroblasts are distinguished from the membrane surface (perichondrium), this will result in the addition of cartilage size (cartilage can increase in size through apposition growth).
Chondrocytes enlarge, divide and produce a matrix. Cell growth continues and produces a matrix, which causes an increase in the size of cartilage mass from within. Growth that causes size increase from the inside is called interstitial growth.
The matrix remains uncalcified: cartilage matrix is rich of chondroitin sulfate which is associated with non-collagen proteins. Nutrition and metabolic waste are discharged directly through the soft matrix to and from the cell. Therefore, blood vessels aren’t needed in cartilage.
The membrane covers the surface but is not essential: cartilage has a closed membrane vascularization called perichondrium, but cartilage can exist without any of these. This property makes cartilage able to grow and adapt where it needs pressure (in the joints), so that cartilage can receive pressure.
Endochondral ossification begins with characteristic changes in cartilage bone cells (hypertrophic cartilage) and the environment of the intercellular matrix (calcium laying), the formation which is called as primary spongiosa. Blood vessels and mesenchymal tissues then penetrate into this area from the perichondrium. The binding tissue cells then differentiate into osteoblasts and cells. Chondroblasts erode cartilage in a cave-like pattern (cavity). The remnants of mineralized cartilage the central part of laying the lamellar bone layer.
The osteoid layer is deposited on the calcified spicules remaining from the cartilage and then mineralized to form spongiosa bone, with fine reticular structures that resemble nets that possess cartilage fragments between the spicular bones. Spongy bones can turn into compact bones by filling empty cavities. Both endochondral and perichondral bone growth both take place toward epiphyses and joints. In the bone lengthening process during endochondral ossification depends on the growth of epiphyseal cartilage. When the epiphyseal line has been closed, the bone will not increase in length. Unlike bone, cartilage bone growth is based on apposition and interstitial growth. In areas where cartilage bone is covered by bone, various variations of zone characteristics, based on the developmental stages of each individual, can differentiate which then continuously merge with each other during the conversion process. Environmental influences (co: mechanism of orthopedic functional tools) have a strong effect on condylar cartilage because the bone is located more superficially .
Cartilage bone height development occurs during the third month of intra uterine life. Cartilage plate extends from the nasal bone capsule posteriorly to the foramen magnum at the base of the skull. It should be noted that cartilages which close to avascular tissue have internal cells obtained from the diffusion process from the outermost layer. This means that the cartilage must be flatter. In the early stages of development, the size of a very small embryo can form a chondroskeleton easily in which the further growth preparation occurs without internal blood supply .
During the fourth month in the uterus, the development of vascular elements to various points of the chondrocranium (and other parts of the early cartilage skeleton) becomes an ossification center, where the cartilage changes into an ossification center, and bone forms around the cartilage. Cartilage continues to grow rapidly but it is replaced by bone, resulting in the rapid increase of bone amount. Finally, the old chondrocranium amount will decrease in the area of cartilage and large portions of bone, assumed to be typical in ethmoid, sphenoid, and basioccipital bones. The cartilage growth in relation to skeletal bone is similar as the growth of the limbs [1, 3].
Longitudinal bone growth is accompanied by remodeling which includes appositional growth to thicken the bone. This process consists of bone formation and reabsorption. Bone growth stops around the age of 21 for males and the age of 18 for females when the epiphyses and diaphysis have fused (epiphyseal plate closure).
Normal bone growth is dependent on proper dietary intake of protein, minerals and vitamins. A deficiency of vitamin D prevents calcium absorption from the GI tract resulting in rickets (children) or osteomalacia (adults). Osteoid is produced but calcium salts are not deposited, so bones soften and weaken.
At the length of the long bones, the reinforcement plane appears in the middle and at the end of the bone, finally produces the central axis that is called the diaphysis and the bony cap at the end of the bone is called the epiphysis. Between epiphyses and diaphysis is a calcified area that is not calcified called the epiphyseal plate. Epiphyseal plate of the long bone cartilage is a major center for growth, and in fact, this cartilage is responsible for almost all the long growths of the bones. This is a layer of hyaline cartilage where ossification occurs in immature bones. On the epiphyseal side of the epiphyseal plate, the cartilage is formed. On the diaphyseal side, cartilage is ossified, and the diaphysis then grows in length. The epiphyseal plate is composed of five zones of cells and activity [3, 4].
Near the outer end of each epiphyseal plate is the active zone dividing the cartilage cells. Some of them, pushed toward diaphysis with proliferative activity, develop hypertrophy, secrete an extracellular matrix, and finally the matrix begins to fill with minerals and then is quickly replaced by bone. As long as cartilage cells multiply growth will continue. Finally, toward the end of the normal growth period, the rate of maturation exceeds the proliferation level, the latter of the cartilage is replaced by bone, and the epiphyseal plate disappears. At that time, bone growth is complete, except for surface changes in thickness, which can be produced by the periosteum . Bones continue to grow in length until early adulthood. The lengthening is stopped in the end of adolescence which chondrocytes stop mitosis and plate thins out and replaced by bone, then diaphysis and epiphyses fuse to be one bone (Figure 7). The rate of growth is controlled by hormones. When the chondrocytes in the epiphyseal plate cease their proliferation and bone replaces the cartilage, longitudinal growth stops. All that remains of the epiphyseal plate is the epiphyseal line. Epiphyseal plate closure will occur in 18-year old females or 21-year old males.
The cartilage found in the epiphyseal gap has a defined hierarchical structure, directly beneath the secondary ossification center of the epiphysis. By close examination of the epiphyseal plate, it appears to be divided into five zones (starting from the epiphysis side) (Figure 8) :
The resting zone: it contains hyaline cartilage with few chondrocytes, which means no morphological changes in the cells.
The proliferative zone: chondrocytes with a higher number of cells divide rapidly and form columns of stacked cells parallel to the long axis of the bone.
The hypertrophic cartilage zone: it contains large chondrocytes with cells increasing in volume and modifying the matrix, effectively elongating bone whose cytoplasm has accumulated glycogen. The resorbed matrix is reduced to thin septa between the chondrocytes.
The calcified cartilage zone: chondrocytes undergo apoptosis, the thin septa of cartilage matrix become calcified.
The ossification zone: endochondral bone tissue appears. Blood capillaries and osteoprogenitor cells (from the periosteum) invade the cavities left by the chondrocytes. The osteoprogenitor cells form osteoblasts, which deposit bone matrix over the three-dimensional calcified cartilage matrix.
When bones are increasing in length, they are also increasing in diameter; diameter growth can continue even after longitudinal growth stops. This is called appositional growth. The bone is absorbed on the endosteal surface and added to the periosteal surface. Osteoblasts and osteoclasts play an essential role in appositional bone growth where osteoblasts secrete a bone matrix to the external bone surface from diaphysis, while osteoclasts on the diaphysis endosteal surface remove bone from the internal surface of diaphysis. The more bone around the medullary cavity is destroyed, the more yellow marrow moves into empty space and fills space. Osteoclasts resorb the old bone lining the medullary cavity, while osteoblasts through intramembrane ossification produce new bone tissue beneath the periosteum. Periosteum on the bone surface also plays an important role in increasing thickness and in reshaping the external contour. The erosion of old bone along the medullary cavity and new bone deposition under the periosteum not only increases the diameter of the diaphysis but also increases the diameter of the medullary cavity. This process is called modeling (Figure 9) [3, 4, 15].
Recent research reported that bone microstructure is also the principle of bone function, which regulates its mechanical function. Bone tissue function influenced by many factors, such as hormones, growth factors, and mechanical loading. The microstructure of bone tissue is distribution and alignment of biological apatite (BAp) crystallites. This is determined by the direction of bone cell behavior, for example cell migration and cell regulation. Ozasa et al. found that artificial control the direction of mesenchymal stem cell (MSCs) migration and osteoblast alignment can reconstruct bone microstructure, which guide an appropriate bone formation during bone remodeling and regeneration .
Bone development begins with the replacement of collagenous mesenchymal tissue by bone. Generally, bone is formed by endochondral or intramembranous ossification. Intramembranous ossification is essential in the bone such as skull, facial bones, and pelvis which MSCs directly differentiate to osteoblasts. While, endochondral ossification plays an important role in most bones in the human skeleton, including long, short, and irregular bones, which MSCs firstly experience to condensate and then differentiate into chondrocytes to form the cartilage growth plate and the growth plate is then gradually replaced by new bone tissue [3, 8, 12].
MSC migration and differentiation are two important physiological processes in bone formation. MSCs migration raise as an essential step of bone formation because MSCs initially need to migrate to the bone surface and then contribute in bone formation process, although MSCs differentiation into osteogenic cells is also crucial. MSC migration during bone formation has attracted more attention. Some studies show that MSC migration to the bone surface is crucial for bone formation . Bone marrow and periosteum are the main sources of MSCs that participate in bone formation .
In the intramembranous ossification, MSCs undergo proliferation and differentiation along the osteoblastic lineage to form bone directly without first forming cartilage. MSC and preosteoblast migration is involved in this process and are mediated by plentiful factors in vivo and in vitro. MSCs initially differentiate into preosteoblasts which proliferate near the bone surface and secrete ALP. Then they become mature osteoblasts and then form osteocytes which embedded in an extracellular matrix (ECM). Other factors also regulate the intramembranous ossification of MSCs such as Runx2, special AT-rich sequence binding protein 2 (SATB 2), and Osterix as well as pathways, like the wnt/β-catenin pathway and bone morphogenetic protein (BMP) pathway [17, 19].
In the endochondral ossification, MSCs are first condensed to initiate cartilage model formation. The process is mediated by BMPs through phosphorylating and activating receptor SMADs to transduce signals. During condensation, the central part of MSCs differentiates into chondrocytes and secretes cartilage matrix. While, other cells in the periphery, form the perichondrium that continues expressing type I collagen and other important factors, such as proteoglycans and ALP. Chondrocytes undergo rapid proliferation. Chondrocytes in the center become maturation, accompanied with an invasion of hypertrophic cartilage by the vasculature, followed by differentiation of osteoblasts within the perichondrium and marrow cavity. The inner perichondrium cells differentiate into osteoblasts, which secrete bone matrix to form the bone collar after vascularization in the hypertrophic cartilage. Many factors that regulate endochondral ossification are growth factors (GFs), transforming growth factor-β (TGF-β), Sry-related high-mobility group box 9 (Sox9) and Cell-to-cell interaction [17, 19].
Osteogenesis/ossification is the process in which new layers of bone tissue are placed by osteoblasts.
During bone formation, woven bone (haphazard arrangement of collagen fibers) is remodeled into lamellar bones (parallel bundles of collagen in a layer known as lamellae)
Periosteum is a connective tissue layer on the outer surface of the bone; the endosteum is a thin layer (generally only one layer of cell) that coats all the internal surfaces of the bone
Major cell of bone include: osteoblasts (from osteoprogenitor cells, forming osteoid that allow matrix mineralization to occur), osteocytes (from osteoblasts; closed to lacunae and retaining the matrix) and osteoclasts (from hemopoietic lineages; locally erodes matrix during bone formation and remodeling.
The process of bone formation occurs through two basic mechanisms:
Intramembranous bone formation occurs when bone forms inside the mesenchymal membrane. Bone tissue is directly laid on primitive connective tissue referred to mesenchyma without intermediate cartilage involvement. It forms bone of the skull and jaw; especially only occurs during development as well as the fracture repair.
Endochondral bone formation occurs when hyaline cartilage is used as a precursor to bone formation, then bone replaces hyaline cartilage, forms and grows all other bones, occurs during development and throughout life.
During interstitial epiphyseal growth (elongation of the bone), the growth plate with zonal organization of endochondral ossification, allows bone to lengthen without epiphyseal growth plates enlarging zones include:
Zone of resting.
Zone of proliferation.
Zone of hypertrophy.
Zone of calcification.
Zone of ossification and resorption.
During appositional growth, osteoclasts resorb old bone that lines the medullary cavity, while osteoblasts, via intramembranous ossification, produce new bone tissue beneath the periosteum.
Mesenchymal stem cell migration and differentiation are two important physiological processes in bone formation.
The author is grateful to Zahrona Kusuma Dewi for assistance with preparation of the manuscript.
The authors declare that there is no conflict of interests regarding the publication of this paper.
alkaline phosphatase biological apatite bone morphogenetic protein extracellular matrix growth factors mesenchymal stem cells runt-related transcription factor 2 special AT-rich sequence binding protein 2 sry-related high-mobility group box 9 transforming growth factor-β
bone morphogenetic protein
mesenchymal stem cells
runt-related transcription factor 2
special AT-rich sequence binding protein 2
sry-related high-mobility group box 9
transforming growth factor-β