**Advances in Bone Tissue Engineering**

Chao Le Meng Bao, Erin Y. Teo, Mark S.K. Chong, Yuchun Liu, Mahesh Choolani and Jerry K.Y. Chan

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/55916

**1. Introduction**

#### **1.1. The need for engineered bone**

While bone is inherently capable of regeneration, complications such as excessive bone loss impede healing, necessitating the use of bone grafts. In the United States alone, an estimated 15 million fractures occurs annually, including 1.6 million hospital admissions for traumatic fractures and 2 million osteoporotic fractures, costing over 60 billion dollars and calling for 1.6 million bone grafts each year [1]; a growing demand for bone grafts is similarly observed worldwide. In such applications, autologous bone grafts continue to be regarded as the "gold standard" for bone repair. However, this may not be practicable in cases involving large bone loss. Additionally, patients suffer from significant donor site morbidity, as well as poor outcomes in older patients [2, 3]. Allogeneic bone grafts may alternatively be used, but pose potential risks of immune rejection and pathogen transmission [4]. Additionally, the limited number of donors is unable to cope with the clinical demand. Consequently, alternative approaches to provide efficacious and reliable bone grafts are being actively pursued.

The advent of tissue engineering, where the aim is to generate functional tissue, has raised the possibility of engineering bone in vitro [5]. Over the past few decades, a wealth of progress in bone tissue engineering has been achieved, particularly in cell sources, developing biocom‐ patible and biodegradable scaffolds, designing bioreactors to enhance in vitro osteogenic priming, and identifying growth factors that can induce or promote endogenous bone and vascular formation [6]. Numerous pre-clinical trials with various animal models have pro‐ duced optimistic results [7].Despite the initial optimism, the lack of translation into a clinical setting suggests significant issues remain, including optimisation of cell sources, choice of biomaterial, in vitro preparation and the mode of delivery.

© 2013 Bao et al.; licensee InTech. This is an open access article 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. © 2013 The Author(s). Licensee InTech. 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.

#### **1.2. Normal bone anatomy**

As seen in figure 1, bone tissue is organised into cancellous or cortical bone. Cancellous bone (also referred to as trabecular bone or spongy bone), is porous, providing structural support and organisation for bone marrow interspersed inside. In contrast, cortical bone is the compact bone surrounding the marrow space, and confers mechanical strength to bone. The outer layer that covers the surface of cortical bones is the periosteum, containing mainly blood vessels and osteoblasts, which are activated during appositional growth and bone repair [8].

**Figure 1.** Schematic overview of bone, depicting gross overview, and cellular distribution. (Figures were produced us‐ ing Servier Medical Art) In particular, osteoprogenitors may be found abundantly in the periosteum and bone marrow, where they perform critical roles in bone repair. Additionally, bone is observed to be highly vascularized, in both the intramedullary canal and periosteal region.

The basic functional unit of the cortical bone is the osteon (or haversian system) which contains cells and extracellular matrix organised in a lamellar pattern, surrounding the haversian canal, in which nerves and blood vessels reside [9]. Within the osteon, osteoblasts and the mature osteocytes exist, contributing to the generation and maintenance of ECM that gives bone it's structural strength [10]. These are derived from osteoprogenitors that reside in the bone marrow and periosteum. Also present are the myeloid-derived osteoclasts that mediate bone resorption; further elaboration on the roles and functions of these cells is provided below. Compared to other tissue, the ECM found in bone is highly mineralized to confer mechanical strength. Calcium and phosphate are found in bone ECM in the form of hydroxyapatite crystal (Ca10(PO4)6(OH)2), interspersed with Type I collagen [11], while the exact composition remains to be elucidated [12]. This unique composite of biological molecules (collagen) and inorganic minerals (calcium phosphate) provides bone with high mechanical strength, as well as toughness to resist impact.

#### **1.3. Bone physiology**

**1.2. Normal bone anatomy**

600 Regenerative Medicine and Tissue Engineering

intramedullary canal and periosteal region.

As seen in figure 1, bone tissue is organised into cancellous or cortical bone. Cancellous bone (also referred to as trabecular bone or spongy bone), is porous, providing structural support and organisation for bone marrow interspersed inside. In contrast, cortical bone is the compact bone surrounding the marrow space, and confers mechanical strength to bone. The outer layer that covers the surface of cortical bones is the periosteum, containing mainly blood vessels and

**Figure 1.** Schematic overview of bone, depicting gross overview, and cellular distribution. (Figures were produced us‐ ing Servier Medical Art) In particular, osteoprogenitors may be found abundantly in the periosteum and bone marrow, where they perform critical roles in bone repair. Additionally, bone is observed to be highly vascularized, in both the

The basic functional unit of the cortical bone is the osteon (or haversian system) which contains cells and extracellular matrix organised in a lamellar pattern, surrounding the haversian canal, in which nerves and blood vessels reside [9]. Within the osteon, osteoblasts and the mature osteocytes exist, contributing to the generation and maintenance of ECM that gives bone it's structural strength [10]. These are derived from osteoprogenitors that reside in the bone marrow and periosteum. Also present are the myeloid-derived osteoclasts that mediate bone resorption; further elaboration on the roles and functions of these cells is provided below. Compared to other tissue, the ECM found in bone is highly mineralized to confer mechanical strength. Calcium and phosphate are found in bone ECM in the form of hydroxyapatite crystal (Ca10(PO4)6(OH)2), interspersed with Type I collagen [11], while the exact composition remains

osteoblasts, which are activated during appositional growth and bone repair [8].

Bone is a highly dynamic tissue, which undergoes constant remodelling through one's lifetime. Homeostasis is achieved through the combined actions of osteoprogenitors, osteoblasts, osteocytes, as well as osteoclasts. In general, bone formation is effected through the prolifer‐ ation of osteoprogenitor cells and differentiation into osteoblasts, which are responsible for the regulation of mineralization and collagen production through expression of functional proteins such as osteocalcin and alkaline phosphatase [13, 14]. Osteoblasts which get trapped in the ECM eventually differentiate to mature osteocytes forming syncytial networks that function to support bone structure and metabolism. Bone actively undergoes remodelling in response to environmental stimuli, such as physiologic influences or mechanical forces, in accordance with Wolff's law. This process involves a balance between bone formation as described above, as well as bone resorption by osteoclasts [15], and it is crucial for renewing bone, to maintain bone strength and mineral homeostasis [16].

The bone is able to undergo significant regeneration in response to trauma and fractures. Regeneration progresses through the three phases of inflammation, repair and remodelling [17]. The immune system can be seen to be intricately involved in the process of healing and inflammation is required for effective healing [18]. Subsequently, the repair and remodelling processes are initiated in the periosteum, which contain a rich population of osteoprogenitors and osteocytes that proliferate and migrate to the defect site, forming a bony bridge to effect fracture healing. When this bridging does not happen, hypertrophic non-union occurs, necessitating the use of bone grafts.
