## 1 Introduction  
Periodontal disease caused by bacterial colonization of the subgingival biofilm evokes an inflammatory response, which finally leads to destruction of the periodontal tissues [1] such as the periodontal ligament and alveolar bone [2]. The goal of contemporary periodontal therapy has always aimed at eliminating infection and restoring the periodontal bone defect [3]. Guided tissue regeneration and bone-grafting procedures have been used to regenerate bone within osseous defects, including that of the alveolar bone [4]. Bone-grafting materials are capable of providing a structural scaffold which stimulates and supports bone formation within osseous defects [4, 5]. Additionally,bone grafts have also been reported to promote the formation of cementum and periodontal ligament (PDL), especially when used in periodontal defects [4; 6]. Commonly used bone graft materials are classified as autologous cancellous or cortical bone, allogeneic mineralized or demineralized bone matrix, and synthetic or animal-derived bone substitutes [6]. Autologous bone (autograft) is considered as the \"gold standard\" bone substitute material, as it contains viable osteoblasts and osteoprogenitor cells, which are capable of inducing new bone formation (i.e., osteogenesis). On the one hand, demineralized allogeneic bone (allograft) is considered an osteoinductive material due to the presence of biologically active growth factors and induces differentiation of the host osteoprogenitor cells into osteoblasts [7]. On the other hand, synthetic (alloplast) and animal-derived bone grafts (xenograft) are only osteoconductive scaffolds, which guide the formation of new bone into the osseous defect, from the borders of the defect [4]. Although bone autografts completely satisfy the tenets of bone regeneration and could be termed as the \"gold standard\", they have several clinical shortcomings, [7] including limited supply intra-orally and need for a second surgery at the donor site. In addition, donor site morbidity and restricted availability of autologous bone are significant clinical disadvantages [8]. While banked cadaveric bone allografts and animal-derived xenografts are readily available and are commonly used, their use is constrained by the potential risk of disease transmission and socio-ethnic restrictions [9]. Therefore, it has become desirable to synthesize bone-graft substitutes, which could be used for treating osseous defects. During the last decade, different bone-graft substitutes have been produced, including calcium phosphate based ceramics [10]. Calcium phosphate (CaP) ceramics have generated greater interest in bone regeneration, because of their similarities to the biological composition of natural bone mineral [11; 12]. CaP-based materials, such as hydroxyapatite (HA), tricalcium phosphate (TCP), and biphasic calcium phosphate (BCP) are capable of being synthesized in the form of granules, blocks, or cements [13]. However, one major disadvantage of CaP ceramics is that they are only osteoconductive [14]. Therefore, advances in biomaterials research have focused on the development of composite bone substitutes, in which osteogenic cells or biological factors (e.g., mesenchymal stem cells, bone morphogenic proteins, platelet derived growth factor etc.) are incorporated with the synthetic bone graft materials to induce osteogenesis [14; 15]. Nevertheless, the use of osteogenic cells or biological factors along with osteoconductive bone substitute materials are either technically sensitive or are expensive [15; 16]. Studies have shown that bone regeneration using synthetic bone substitutes can be enhanced through less complicated therapeutic strategies such as application of hyaluronic acid (HyA) [15; 17]. HyA has been reported to be capable of increasing the function of the osteogenic cells [15; 18]. HyA is a critical component of extracellular matrix (ECM) in connective tissue and bone marrow, and it has been proven to play a key role in tissue repair and regeneration [17; 19].