Delivery of Growth Factors to Enhance Bone Repair

Abstract

The management of critical-sized bone defects caused by nonunion, trauma, infection, malignancy, pseudoarthrosis, and osteolysis poses complex reconstruction challenges for orthopedic surgeons. Current treatment modalities, including autograft, allograft, and distraction osteogenesis, are insufficient for the diverse range of pathology encountered in clinical practice, with significant complications associated with each. Therefore, there is significant interest in the development of delivery vehicles for growth factors to aid in bone repair in these settings. This article reviews innovative strategies for the management of critical-sized bone loss, including novel scaffolds designed for controlled release of rhBMP, bioengineered extracellular vesicles for delivery of intracellular signaling molecules, and advances in regional gene therapy for sustained signaling strategies. Improvement in the delivery of growth factors to areas of significant bone loss has the potential to revolutionize current treatment for this complex clinical challenge.

Keywords: BMP; critical-sized defect; gene therapy; growth factor; stem cell.

Figure 1

Radiograph of a tibial critical-sized bone defect associated with a fracture nonunion complicated by infection. The patient status is post-placement of an external fixator with an intramedullary antibiotic device pending distraction osteogenesis (Radiographs courtesy of Dr Joseph Patterson).

Figure 2

Features of an optimized delivery system.

Figure 3

Schematic illustration of a parent cell undergoing ectocytosis of an extracellular vesicle and the engineering strategies to optimize extracellular vesicles (EVs) for bone repair (The figure was created with BioRender.com).

Figure 4

Radiograph of a 6 mm athymic rat critical-sized femoral defect treated with LV-BMP-2 transduced human adipose-derived stem cells loaded on a TCP-HA scaffold at postoperative day 0 (left) with the healed defect at 12 weeks postoperatively (right).

Figure 5

Schematic illustration of two-step transcriptional amplification (TSTA) lentiviral system overexpressing growth factor genes of interest in adipose stem cells. The TSTA system is composed of two separate lentiviral vectors: the GAL4-VP16 (LV-RhMLV-GAL4-VP16) transactivator vector and the transgene vector expressing the growth factor gene (LV-G5-GF gene) (Created with BioRender.com). LV, lentivirus; RhMLV, murine leukemia virus; LTR, long terminal repeat; Ψ, packaging signal; RRE, rev-responsible element; cppt, central polypurine tract; G5 promoter, GAL4 binding site; SIN, self-inactivating; GF, growth factor; ASC, adipose stem cell; BMP-2, bone morphogenetic protein 2.

Figure 6

Human Adipose-Derived Stem Cells transduced with LV-BMP-2 loaded on a scaffold prior to implantation in a critical-sized bone defect. MSCs, mesenchymal stem cells; LV-BMP-2, lentivirus vector expressing bone morphogenetic protein. (The figure was created with BioRender.com).