Clinical application of injectable growth factor for bone regeneration: a systematic review

Abstract

Bone regeneration has been the ultimate goal in the field of bone and joint medicine and has been evaluated through various basic research studies to date. Translational research of regenerative medicine has focused on three primary approaches, which are expected to increase in popularity: cell therapy, proteins, and artificial materials. Among these, the local injection of a gelatin hydrogel impregnated with the protein fibroblast growth factor (FGF)-2 is a biomaterial technique that has been developed in Japan. We have previously reported the efficacy of gelatin hydrogel containing injectable FGF-2 for the regenerative treatment of osteonecrosis of the femoral head. Injectable growth factors will probably be developed in the future and gain popularity as a medical approach in various fields as well as orthopedics. Several clinical trials have already been conducted and have focused on this technique, reporting its efficacy and safety. To date, reports of the clinical application of FGF-2 in revascularization for critical limb ischemia, treatment of periodontal disease, early bone union for lower limb fracture and knee osteotomy, and bone regeneration for osteonecrosis of the femoral head have been based on basic research conducted in Japan. In the present report, we present an extensive review of clinical applications using injectable growth factors and discuss the associated efficacy and safety of their administration.

Keywords: Bone regeneration; Cell proliferation; Clinical trial; Drug delivery system; Fibroblast growth factor; Gelatin hydrogel; Growth factor; Osteonecrosis; Tissue engineering.

Fig. 1

Human figure showing where clinical applications of injectable growth factor are used. Injectable growth factor therapy is actually being performed from the head to toe

Fig. 2

Injectable gelatin hydrogel containing growth factor. The growth factor solution is impregnated in gelatin hydrogel to create a gel-form that can be percutaneously injected using a syringe. a Preparation of the growth factor solution (upper) and the freeze-dried gelatin (lower). b A gel-form of growth factor-impregnated gelatin hydrogel inside the syringe. c Injected gel-form containing growth factor

Fig. 3

Schematic representation of FGF-FGFR signaling pathways and mechanisms in osteogenesis. The regulation of osteogenesis by FGF and FGFR. FGF/FGFR signaling is an important regulator of osteoblastogenesis, and that control osteoblast replication and differentiation. Activation of FGF and FGFR triggers the activation of ERK1/2 MAPK, PLCγ/PKC, and Akt activity which upregulate osteoblast gene expression and osteogenesis. Abbreviations: FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptors

Fig. 4

Percutaneous administration of growth factors into the femoral head. Local injection can be percutaneously administered to the target site. This reduces the operating time and damage to surrounding tissue and enables surgery to be minimally invasive. a A syringe with long needle available for percutaneous administration. b An intraoperative radiographic image reaching to the target site. c An intraoperative photograph when pushing the plunger to inject