1. Introduction

The skeletal system is dynamic, metabolically active and functionally diverse. As well as a structural function, it has a metabolic role. It supports and protects the vital internal organs and is the site of synthesis of the hematopoietic marrow and provides sites of muscle attachment for locomotion. Bone is involved in both mineral metabolism, via calcium and phosphate homeostasis, and acid–base balance, via the buffering of hydrogen ions ^[1]. Moreover, it has been suggested that bone has other important endocrine functions in fertility, glucose metabolism, appetite regulation and muscle function ^[2][3]. The craniofacial area is prone to trauma and pathologies that often result in large bone damage, these leading to both aesthetic and functional complications for patients. Throughout life, the craniofacial area is at risk of complex injuries that require bone grafting to restore function. The etiology of such injuries may be accidental (e.g., acute trauma), congenital (e.g., birth defects or deformities), pathological (e.g., maxillofacial tumors, such as ameloblastoma, or infection) or surgical. Whenever the lesions are extensive, they cause large bone defects that cannot self-repair because they exceed the body’s natural regenerative capacity. The “gold standard” for treating these large defects is autologous bone grafting. Since the defects are extensive, harvesting of the necessary bone at the donor site can cause major morbidity, including bone deformity, as well as pain and occasionally rebound resorption. Tissue engineering has made it possible to approach these issues from another angle.

2. Human Clinical Applications of FGF-2 in the Craniofacial Area

Indeed, rhFGF-2 is already used in the clinical treatment of orofacial tissues. Kitamura et al. ^[4] performed a double-blind randomized controlled trial with 253 patients receiving rhFGF-2 0.2%, 0.3% or 0.4% or placebo during surgical management of periodontal intrabony defects. At 36 weeks, all FGF-2-treated groups demonstrated significantly higher radiographic bone fill than the placebo group, 0.3% being the best concentration. In addition, secondary analysis in a subgroup of patients showed very low levels of FGF-2 in serum and no adverse effects were reported. Another randomized controlled trial of 30 patients showed an improvement in pocket depth reduction and more clinical attachment gain compared to control sites ^[5]. Application of FGF-2 for the treatment of intrabony defects has been studied in another randomized controlled trial, where various concentrations of FGF-2 were used mounted in β-tricalcium phosphate scaffolds. At 6 months, patients treated with 0.3% or 0.4% rhFGF-2 showed 71% success for the combined outcome of attachment gain of 1.5 mm and bone fill of 2.5 mm compared to 45% success in the 0.1% FGF-2 and control groups ^[6]. A meta-analysis of studies using recombinant human FGF-2 for the treatment of deep intrabony periodontal defects demonstrated a clinical benefit of FGF-2 in terms of bone fill ^[7]. A more recent meta-analysis of six randomized controlled trials shows that administration of 0.4% rhFGF-2 yielded 22% higher bone fill of periodontal defects than control treatment, though this result was not statistically significant. It also indicated that the impact of the treatment was dose dependent, with higher FGF-2 concentrations producing better bone regeneration outcomes ^[8]. To date, however, there is still no consensus on the optimal dose or delivery scaffolding method for the use of FGF-2 in the field of bone regeneration.