Gene Therapy in Bone Regeneration: A Summary of Delivery Approaches for Effective Therapies - Intracellular Delivery: Fundamentals and Applications - page 814

Abbreviations

AV Adenovirus

AAV Adeno-Associated Virus

BMP Bone Morphogenetic Protein

FGF Fibroblast Growth Factor

HA Hydroxyapatite

LIPUS Low Intensity Pulsed Ultrasound

NLS Nuclear Localization Signal

NPC Nuclear Pore Complex

OP Osteogenic Protein

PEI Polyethyleneimine

PLGA Poly(lactic-glycolic acid)

PLL Poly- L -lysine

RGD Arginine-Glycine-Aspartic Acid

VEGF Vascular Endothelial Growth Factor

1 Introduction

Musculoskeletal conditions affect one in four Americans, and the combined direct and
indirect costs of bone and joint health are estimated to be nearly $850 billion (AAOS
2010 ). There are approximately 20.2 million musculoskeletal injuries in the United
States annually and up to 20% of fractures are associated with impaired healing
(Verettas et al. 2002 ). Approximately 2.2 million bone grafts are performed world-
wide each year (Giannoudis et al. 2005 ), which places a huge burden on medical
health care systems: spinal fusions alone cost approximately $20 billion annually
(Porter et al. 2009 ). The complex biology of bone healing undoubtedly plays a role in
assurance of successful outcome as well as the complications typically seen. Fracture
healing, as a prototypical bone healing model, is generally divided into four stages
(Marsh and Li 1999 ): hematoma formation and inflammation, soft callus phase, matu-
ration to a hard callus, and remodelling. Following the injury, platelets at the injury
site are activated and produce growth factors to recruit inflammatory cells to the injury
site. Cells involved in repair, such as fibroblasts, pre-osteoblasts and mesenchymal
stem cells, are also recruited. New connective tissue induced after the injury forms a
soft callus, along with a robust angiogenic network. This callus eventually hardens,
either via intramembranous ossification (i.e., osteoblast formation directly from mes-
enchymal stem cells) or endochondral ossification with a cartilage intermediate.
Because the initially deposited woven bone does not have enough mechanical
strength, it is remodelled into stronger laminar bone through the dual efforts of osteo-
blasts and osteoclasts. This complex series of well-coordinated events is orchestrated
by a myriad of growth factors produced by cells involved in the healing process.
Growth factors produced during fracture healing include platelet derived growth fac-
tor (Bourque et al. 1993 ), transforming growth factor-b (Andrew et al. 1993 ), insulin-
like growth factor, vascular endothelial growth factor (Uchida et al. 2003 ) and